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Keywords:

  • excitotoxicity;
  • glutamate;
  • Interleukin-1β;
  • neuroinflammation;
  • oxidative stress;
  • system xc

Abstract

  1. Top of page
  2. Abstract
  3. The interleukin-1 family
  4. Interleukin-1 in the brain
  5. Interleukin-1β and neuronal injury
  6. Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders
  7. Conclusion
  8. Acknowledgments
  9. References

Interleukin-1 (IL-1) is a proinflammatory cytokine released by many cell types that acts in both an autocrine and/or paracrine fashion. While IL-1 is best described as an important mediator of the peripheral immune response during infection and inflammation, increasing evidence implicates IL-1 signaling in the pathogenesis of several neurological disorders. The biochemical pathway(s) by which this cytokine contributes to brain injury remain(s) largely unidentified. Herein, we review the evidence that demonstrates the contribution of IL-1β to the pathogenesis of both acute and chronic neurological disorders. Further, we highlight data that leads us to propose IL-1β as the missing mechanistic link between a potential beneficial inflammatory response and detrimental glutamate excitotoxicity.


Abbreviations used
[glutamate]e

extracellular glutamate concentration

4-CPG

4-carboxyphenylglycine

β-APP

β-amyloid precursor protein

AA

arachidonic acid

AChE

acetylcholinesterase

AD

Alzheimer’s Disease

ALS

Amyotrophic lateral sclerosis

amyloid β

GLT-1

rodent glutamate transporter subtype I

HAD

HIV-associated dementia

HD

Huntington’s Disease

HUVEC

human umbilical vein endothelial cells

ICE

interleukin-1 converting enzyme or caspase-1

IFN

interferon

IL

interleukin

IL-1ra

interleukin-1 receptor antagonist

IL-1RAcP

interleukin-1 receptor accessory protein

IL-1RI

interleukin-1 receptor type I

IL-1RII

interleukin-1 receptor type II

IL-1Rrp

interleukin-1 receptor-related protein

LDF

Laser Doppler Flowmetry

LTP

long-term potentiation

mGluR

metabotropic glutamate receptor

MS

multiple sclerosis

NAC

N-acetyl-cysteine

NFκB

nuclear factor κB

NOS

nitric oxide synthase

OVLT

organum vaculosum laminae terminalis

PLA2

phospholipase A2

rh

recombinant human

ROS

reactive oxygen species

SCI

spinal cord injury

SFO

subfornical organ

SOD

superoxide dismutase

System XAG

sodium-dependent, high affinity glutamate transporters

system xc

cystine-glutamate antiporter or cystine-glutamate transporter

TBI

traumatic brain injury

TNF

tumor necrosis factor

VMPO

ventromedial preoptic area

The interleukin-1 family

  1. Top of page
  2. Abstract
  3. The interleukin-1 family
  4. Interleukin-1 in the brain
  5. Interleukin-1β and neuronal injury
  6. Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders
  7. Conclusion
  8. Acknowledgments
  9. References

Front cover: Glial fibrillary acidic protein immunostaining of mouse cortical astrocytes, exposed to retinoic acid. (see pp. 320–332). Photo: by Dr Jörg Mei, Institut für Biologie II, RWTH Aachen University, Germany.

The canonical interleukin-1 (IL-1) family is composed of three closely related proteins that are products of different genes: two agonists, IL-1α and IL-1β, and a naturally occurring IL-1 receptor antagonist (IL-1ra) [for detailed review, please see Dinarello (1994, 1996, 1998, 2002)]. In humans, IL-1α, IL-1β, and IL-1ra are encoded by the IL1A, IL1B, and IL1-RN genes, respectively, all located on the long arm of chromosome 2 (Webb et al. 1986; Modi et al. 1988; Lafage et al. 1989; Lennard et al. 1992; Steinkasserer et al. 1992; Patterson et al. 1993). Several new IL-1 family members, including IL-18 (Okamura et al. 1995; Bazan et al. 1996) and IL-1F5-11 (Debets et al. 2001; Nicklin et al. 2002; Taylor et al. 2002; Towne et al. 2004; Schmitz et al. 2005) have been identified based on gene homology, gene location, and receptor binding [for review, see Dunn et al. (2001); Dinarello (2002)]. Of the new family members, the most extensively studied is IL-18, which signals via binding through IL-1 receptor 18, also known as IL-1 receptor-related protein (IL-1Rrp) (Parnet et al. 1996; Torigoe et al. 1997). Activation of this receptor leads to induction and release of several pro-inflammatory cytokines [e.g., IL-6, IL-8, tumor necrosis factor (TNF)α, IL-1β, interferon (IFN)γ] (Dinarello 2002; Gracie et al. 2003). Hence, IL-18 signaling may contribute to tissue destruction in several inflammatory disorders (Dinarello 2002). It may also contribute to neuropathology [for review, see Felderhoff-Mueser et al. (2005)]. IL-1F6, IL-1F8, and IL-1F9 signal via a newly described receptor designated IL-1Rrp2 (Lovenberg et al. 1996; Towne et al. 2004), leading to activation of signaling pathways (i.e., mitogen-activated protein kinase and nuclear factor (NF)-κB activation) and downstream effectors (i.e., IL-6 release) similar to those activated by IL-1 (Towne et al. 2004). Since these ligands and their receptor are predominantly expressed in the skin and airways, it has been proposed that they represent the first line of defense against entering pathogens (Debets et al. 2001; Towne et al. 2004). IL-1F11, also known as IL-33, signals via activation of the IL-33 receptor ST2, resulting in increased production of IL-5 and IL-13, as well as reduced IFNγ release (Schmitz et al. 2005). Signaling pathways for IL-1F5 and IL-1F7 have yet to be elucidated. Interestingly, it appears that IL-1F5 resulted from a gene duplication of IL-1ra (Taylor et al. 2002). However, it does not appear to function as an IL-1RI antagonist, since it neither blocks IL-1α nor IL-1β-induced IL-6 production (Towne et al. 2004). Whether these new family members contribute to the pathogenesis or resolution of neurological disorders remains to be fully defined. Hence, this review will focus on the conventional (i.e., original) members of the IL-1 family, highlighting their potential to influence – both positively and negatively – neuropathological processes.

IL-1α and IL-1β share ≈ 30% structural homology and are both produced as 33 kDa precursors (Giri et al. 1985). While each can be cleaved to a 17 kDa ‘mature’ form by intracellular or extracellular proteases, most (≈ 90%) of IL-1α remains in the cytosol of cells in its precursor form or is transported to the cell surface where it remains membrane associated (Endres et al. 1989; Lonnemann et al. 1989). This membrane bound form may become activated and released following cleavage by an extracellular protease, perhaps now acting as a paracrine messenger to adjacent cells (Endres et al. 1989; Lonnemann et al. 1989; Dinarello and Wolff 1993). However, considering the intranuclear localization of IL-1α (Grenfell et al. 1989; Curtis et al. 1990), it has also been suggested that intracellular pro-IL-1α may directly function as a gene regulator (Maier et al. 1990; Kawaguchi et al. 2006). In contrast to IL-1α, proteolytic cleavage is required for biological activity of IL-1β whereby ≈ 80% of processed IL-1β– performed by the IL-1β-converting enzyme (ICE), also known as caspase-1 (Cerretti et al. 1992; Thornberry et al. 1992) – is released by the cell into the extracellular space (Dinarello 1996). Interestingly, IL-1 proteins, in general, lack the hydrophobic signal sequence (i.e., leader sequence) that targets most secreted proteins to the endoplasmic reticulum (Auron et al. 1984; Lomedico et al. 1984; March et al. 1985; Gray et al. 1986; Young and Sylvester 1989). Hence, it is unknown exactly how IL-1β is secreted, but it has been suggested that this can occur via exocytosis, active transport by a multi-drug resistance transporter, and/or following cell death (Hogquist et al. 1991; Griffiths et al. 1995; Singer et al. 1995; Ferrari et al. 1997; MacKenzie et al. 2001; Le Feuvre et al. 2002a,b; Andrei et al. 2004; Bianco et al. 2005; Brough and Rothwell 2007).

Despite being only 30% homologous, both mature IL-1α and IL-1β can exhibit an essentially identical repertoire of functions when presented exogenously (Dinarello and Thompson 1991; Dinarello 1998), although notable exceptions to this have been reported (Uehara et al. 1987; da Cunha et al. 1993; Juric and Carman-Krzan 2001). Binding to a specific 80 kDa plasma membrane receptor, designated the IL-1 receptor type I (IL-1RI) (Sims et al. 1993; Martin and Falk 1997; Loddick et al. 1998) facilitates the interaction with IL-1 receptor accessory protein (IL-1RAcP) (Wesche et al. 1997; Zetterstrom et al. 1998), which together induces downstream signaling pathways [for detailed review, see Sims and Dower (1994); Dinarello (1998); Martin and Wesche (2002); Li and Qin (2005)]. A second receptor designated IL-1 receptor type II (IL-1RII) can bind IL-1 but since it lacks the intracellular domain, it cannot signal. It functions biologically as a sink for IL-1β– it has a 10–100-fold lower affinity for IL-1α– and has been termed a decoy receptor (Colotta et al. 1993). Despite this, antibody blocking studies suggest that signaling through IL-1RII could mediate the febrile response as well as prostaglandin E2 release from hypothalamic explants elicited via exogenous administration of IL-1β (Luheshi et al. 1993; Mirtella et al. 1995). However, the specificity of this antibody to IL-1RII has been disputed (Gayle et al. 1994) and a very recent study using an endothelial-specific knockdown of IL-1RI calls the former observation into question (Ching et al. 2007). Nevertheless, whether an alternative signaling pathway (i.e., an as yet unidentified functional receptor for IL-1) exists remains unresolved (Desson and Ferguson 2003; Diem et al. 2003; Andre et al. 2006).

The third member of the IL-1 family, IL-1ra, serves to competitively inhibit IL-1α or IL-1β binding to IL-1RI and hence subsequent receptor signaling (Dripps et al. 1991; Dinarello 1998). However, it should be noted that high concentrations of IL-1ra relative to IL-1 are needed to block IL-1-mediated signal transduction [≈ 100-fold excess (Wakabayashi et al. 1991)] and an up-regulation of IL-1ra – as observed following CNS injury (Wang et al. 1997b) – may not be sufficient to counteract the effects of injury-induced IL-1 release. Additionally, the ligand binding portion of IL-1 receptors (both RI and RII) can be shed from the plasma membrane as soluble receptors where they are able to bind to circulating IL-1(α or β) with high avidity, thereby inhibiting the interaction between IL-1 and the cell surface IL-1RI (Roux-Lombard 1998). Given the potent biological activity of IL-1 – only a few receptors (in some cells < 10) need to be occupied for signaling to occur (Orencole and Dinarello 1989) – this regulation may be important to prevent initiation of potentially maladaptive inflammatory signaling processes.

Interleukin-1 in the brain

  1. Top of page
  2. Abstract
  3. The interleukin-1 family
  4. Interleukin-1 in the brain
  5. Interleukin-1β and neuronal injury
  6. Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders
  7. Conclusion
  8. Acknowledgments
  9. References

All members of the IL-1 family (i.e., IL-1, IL-1ra, IL-1RI, IL-1RII, and IL-1RAcP) are expressed in the healthy CNS. Low levels of IL-1β immunoreactivity have been detected throughout the brain of rodents, with highest expression occurring in the hippocampus, hypothalamus, and basal forebrain (Breder et al. 1988; Lechan et al. 1990; Molenaar et al. 1993). IL-1RI has also been shown to be expressed throughout the brain, with highest levels found in cerebral cortex and hippocampus (Farrar et al. 1987; Takao et al. 1990; French et al. 1999). The cell types capable of synthesizing IL-1 – microglia (Giulian et al. 1986; Hetier et al. 1988; Yao et al. 1992), astrocytes (Lieberman et al. 1989; Knerlich et al. 1999; Zhang et al. 2000), oligodendrocytes (Blasi et al. 1999), and neurons (Lechan et al. 1990; Takao et al. 1990; Watt and Hobbs 2000) – also express the signaling receptor (Ban et al. 1993; Cunningham and De Souza 1993; Wong and Licinio 1994; Tomozawa et al. 1995; Blasi et al. 1999; French et al. 1999; Hammond et al. 1999; Friedman 2001; Pinteaux et al. 2002; Wang et al. 2006). While the original studies failed to establish the presence of IL-1RI in brain vascular cells (Diana et al. 1999; French et al. 1999), Konsman and colleagues demonstrate IL-1RI-immunoreactive vessels throughout the brain with concentrated expression on brain venules of the circumventricular organs (OVLT, VMPO, SFO) and low level staining in all other areas (Konsman et al. 2004). IL-1RII shows a very similar expression pattern as IL-1RI, except for in the hypothalamus, where it appears to be the more abundant (French et al. 1999). Finally, IL-1RAcP – the protein necessary for signal transduction via IL-1RI to occur – is also expressed in the rat brain under normal physiological conditions with particularly high levels in the hypothalamus, cortex, hippocampus, and cerebellum (Liu et al. 1996; Ilyin et al. 1998). Expression of IL-1α and β, IL-1ra, and IL-1 receptors has also been demonstrated in postmortem human brain (Sheng et al. 1998a; Huitinga et al. 2000; Toyooka et al. 2003). Although cell type-specific expression of the IL-1 family in human tissue has not been investigated thoroughly, IL-1 and IL-1ra RNA can be detected in cultured human microglia (Walker et al. 1995) and IL-1 immunoreactivity is present in human neurons (Huitinga et al. 2000).

Interestingly, IL-1α, IL-1β, and IL-1RI knockout mice show no gross physiological or developmental defects (Glaccum et al. 1997; Horai et al. 1998), which might suggest that IL-1 has little or no function in healthy tissue but functions mostly in disease states. However, the above-described expression pattern suggests that – along with its more accepted role in mediating immune reactions – IL-1 may modulate neuronal activity either inter-neuronally or via neuron-glia interactions. In fact, several studies have investigated the role of endogenous IL-1 in classic models of neuroplasticity such as long-term potentiation (LTP), an experimentally induced increase in synaptic strength that is believed to underlie certain forms of learning and memory (Bliss and Collingridge 1993). Following induction of LTP via high frequency stimulation in the hippocampus of freely moving rats, as well as in hippocampal slice preparations, IL-1β gene expression is significantly increased (Schneider et al. 1998; Balschun et al. 2003). Importantly, inhibition of IL-1β signaling by exogenous addition of IL-1ra prevents the induction and maintenance of LTP in the Schaffer collaterals in vitro (Schneider et al. 1998; Ross et al. 2003), as well as maintenance – but not induction – of LTP in the perforant path in vivo (Schneider et al. 1998). Finally, mice lacking IL-1RI lack long-term potentiation induced by either high frequency stimulation of the perforant path or by theta burst stimulation of the Schaffer collaterals in vitro (Avital et al. 2003). They also exhibit marked learning impairments measured by poorer performance in the Morris water maze (a hippocampus-dependent task) (Avital et al. 2003).

A role for IL-1 signaling in the regulation of sleep patterns has also been suggested [for review, see Krueger et al. (2001); Obal and Krueger (2003); Kapsimalis et al. (2005)]. IL-1β mRNA levels in the brain of rats are highest at the onset of non-rapid eye movement sleep (Taishi et al. 1997). Intracerebroventricular injection of either IL-1ra (Opp and Krueger 1991) or an antibody directed against IL-1β (Opp and Krueger 1994a,b) significantly reduces NREMS. Finally, IL-1RI-deficient mice sleep less than their wild-type controls (Fang et al. 1998; Krueger et al. 1998). Interestingly, IL-1β blood levels correlate with the onset of NREMS in humans as well, suggesting that this may not be just an experimental phenomenon (Moldofsky et al. 1986).

Interleukin-1β and neuronal injury

  1. Top of page
  2. Abstract
  3. The interleukin-1 family
  4. Interleukin-1 in the brain
  5. Interleukin-1β and neuronal injury
  6. Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders
  7. Conclusion
  8. Acknowledgments
  9. References

The inflammatory response is intended as a cellular defense mechanism to remove or inactivate harmful agents. While most studies suggest that IL-1β signaling is harmful to the injured CNS (Relton and Rothwell 1992; Toulmond and Rothwell 1995; Yamasaki et al. 1995; Betz et al. 1996; Relton et al. 1996; Yang et al. 1997; Boutin et al. 2001; Nesic et al. 2001; Tehranian et al. 2002; Jones et al. 2005; Lu et al. 2005), some report neuroprotective effects that appear to be dependent on the concentration of cytokine and the timing of the response relative to insult (Strijbos and Rothwell 1995; Ohtsuki et al. 1996; Carlson et al. 1999; Wang et al. 2000; Pringle et al. 2001; Bernardino et al. 2005; Shaftel et al. 2007b). Importantly, IL-1β alone, in the absence of additional CNS impairment, is not neurotoxic (Relton and Rothwell 1992; Yamasaki et al. 1995; Loddick and Rothwell 1996; Lawrence et al. 1998; Rothwell 1999; Shaftel et al. 2007a). Considering this, we propose that the increase in IL-1β expression that occurs after insult/injury is part of a protective response that ultimately goes awry. Indeed, changes in IL-1 expression and/or signaling are associated with the pathogenesis of many neurological disorders [for review, see Allan and Rothwell (2001); Allan et al. (2005)]. The fact that many neurological disorders share common mechanisms of injury could provide potential clues to the mechanisms underlying the detrimental effects of IL-1β. For instance, disturbances of glutamatergic transmission leading to excitotoxic cell death contribute to neuronal loss in both acute neurological injuries and chronic neurodegenerative diseases (Choi 1988; Meldrum and Garthwaite 1990; Benveniste 1991; Beal 1992; Coyle and Puttfarcken 1993; Lipton and Rosenberg 1994; Nakao and Brundin 1998) and evidence has emerged on the interplay between IL-1β and glutamate excitotoxicity (Relton and Rothwell 1992; Lawrence et al. 1998; Stroemer and Rothwell 1998; Pearson et al. 1999; Allan et al. 2000; Jander et al. 2000, 2001). Oxidative stress also occurs in many neurological diseases (Beal 1995; Owen et al. 1996; Behl and Moosmann 2002; Cookson et al. 2002; Barnham et al. 2004; Steiner et al. 2006; Conti et al. 2007) and can be linked to both excitotoxicity (Lafon-Cazal et al. 1993b; Marin et al. 1993; Reynolds and Hastings 1995; Hazell 2007) and IL-1β (Troy et al. 1996; Viviani et al. 2001; Brabers and Nottet 2006). Hence, it is intriguing to speculate that glutamate toxicity, oxidative stress, and IL-1β are inextricably linked. In the following sections, we will discuss evidence for this theory.

Excitotoxicity

Glutamate is the major neurotransmitter of the mammalian CNS (Fonnum 1984). Maintenance of extracellular glutamate concentrations ([glutamate]e) within a narrow physiological range involves control of its release as well as its uptake and is necessary to protect neurons from excitotoxic injury. Dysregulation of numerous cellular processes may contribute to a pathological rise in [glutamate]e including: (i) increased exocytotic vesicular release (Drejer et al. 1985; Katayama et al. 1991; Monyer et al. 1992; Wahl et al. 1994; Jabaudon et al. 1999); (ii) loss or diminished function of sodium-dependent glial glutamate transporters (system XAG) (Balcar and Li 1992; Rothstein et al. 1996; Brown 1999; Jabaudon et al. 1999, 2000; Danbolt 2001); (iii) reversal of these same transporters resulting in glutamate release rather than clearance (Nicholls and Attwell 1990; Szatkowski et al. 1990; Szatkowski and Attwell 1994; Longuemare and Swanson 1995; Seki et al. 1999; Phillis et al. 2000; Hamann et al. 2002); (iv) opening of astrocytic volume-sensitive organic anion channels (Kimelberg et al. 1990; Rutledge et al. 1998; Seki et al. 1999; Kimelberg et al. 2004); (v) opening of astrocytic hemichannels (Ye et al. 2003); and (vi) increased activity of the cystine/glutamate exchanger (system xc) (Piani and Fontana 1994; Ye and Sontheimer 1999; Barger and Basile 2001; Fogal et al. 2007).

Several lines of evidence suggest that excitotoxicity and IL-1β are not mutually exclusive. First, IL-1β expression in microglia and astrocytes increases in the cortex and striatum of rats following NMDA-induced excitotoxicity (Pearson et al. 1999). Second, NMDA receptor antagonism can suppress IL-1β expression following both cerebral ischemia (Jander et al. 2000) and high K+-induced cortical spreading depression (Jander et al. 2001), thus begging the question as to whether IL-1β modulates ischemic damage by modulating excitotoxic neuronal injury. Experimental evidence would support this notion. Intrastriatal application of IL-1ra can reduce the lesion size induced by direct NMDA receptor activation (Relton and Rothwell 1992). Furthermore, IL-1β injected into the striatum of rats does not cause neuronal cell death itself, but enhances excitotoxic neuronal injury in both the striatum and cortex (Lawrence et al. 1998; Stroemer and Rothwell 1998; Allan et al. 2000).

While the above data suggest a link between IL-1β and glutamate toxicity, the mechanism(s) by which these detrimental pathways converge may be diverse. For instance, IL-1β has been demonstrated to directly increase the activity of hippocampal neuronal NMDA receptors via phosphorylation of the NR2A/B subunit in a manner sufficient to increase NMDA-induced neuronal cell death (Viviani et al. 2003). Prolonged treatment of human astrocytes with IL-1β has been reported to decrease the expression of the glial glutamate transporter subtype I (GLT-1), ultimately leading to a functional decrease in glutamate uptake (Hu et al. 2000). And, we recently showed that IL-1β treatment of mixed cortical neuron-astrocyte co-cultures results in increased glutamate export via system xc (Fogal et al. 2007). Additionally, IL-1β induces the production of several factors, which are associated with glutamate toxicity, and are known to participate in the pathology of several neurological disorders, including nitric oxide synthase (NOS) and arachidonic acid (AA) (Dayton and Major 1996; Stella et al. 1997; McCann et al. 1998; Satta et al. 1998; Sung et al. 2004). With respect to the former, induction of NOS-2 in mixed murine cortical neuron-astrocyte co-cultures increases [glutamate]e during oxygen-glucose deprivation via increased exocytosis (Hewett et al. 1996; Vidwans and Hewett 2004). Similarly, AA can contribute to the buildup of glutamate in the synaptic cleft by increasing its release (Lynch and Voss 1990; Vazquez et al. 1994), and by decreasing its uptake (Yu et al. 1987; Barbour et al. 1989). In addition, AA can directly enhance NMDA receptor function via increases in NMDA receptor channel open probability (Miller et al. 1992). Hence, it appears likely that several IL-1β-stimulated pathways converge upon glutamate excitotoxicity.

Oxidative stress

The formation of reactive oxygen species (ROS) is also well recognized as a mechanism of tissue damage in several neurological disorders (Emerit et al. 2004; Van Damme et al. 2005; Browne and Beal 2006; Jenner and Olanow 2006). Interestingly, accumulation of ROS and increased IL-1β levels may be linked (Troy et al. 1996; Viviani et al. 2001; Brabers and Nottet 2006). A recent study demonstrated that ROS themselves can increase/induce cellular IL-1β in mixed hippocampal cultures (Brabers and Nottet 2006). In support, plasminogen-induced IL-1β production in microglia is reduced in the presence of the antioxidants trolox or N-acetyl-cysteine (NAC) (Min et al. 2003). Additionally, reduction of superoxide dismutase (SOD)-1 in PC12 cells, which would presumably lead to an increase in ROS production, increases IL-1β expression (Troy et al. 1996). Intriguingly, NMDA receptor activation in vitro results in the formation of ROS (Lafon-Cazal et al. 1993a; Dugan et al. 1995; Reynolds and Hastings 1995) and inhibition of lipid peroxidation – an important contributor to oxidative stress – reduces IL-1β expression and reduces glutamate receptor toxicity in vivo (Marini et al. 2004). As oxidant stress is a specific and important inducer of IL-1β expression (Troy et al. 1996; Viviani et al. 2001; Min et al. 2003; Brabers and Nottet 2006) and a product of excitotoxicity (Lafon-Cazal et al. 1993a; Dugan et al. 1995; Reynolds and Hastings 1995), evidence again suggests a mechanistic link.

Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders

  1. Top of page
  2. Abstract
  3. The interleukin-1 family
  4. Interleukin-1 in the brain
  5. Interleukin-1β and neuronal injury
  6. Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders
  7. Conclusion
  8. Acknowledgments
  9. References

An increase in IL-1β expression has been associated with neuronal injury in both acute and chronic age-related degenerative neurological diseases. In the following sections, we will review the evidence for a role of IL-1β in their pathology and highlight the relationship between IL-1, oxidative stress, and glutamate toxicity.

Acute neurological disorders

Interleukin-1 and cerebral ischemia

IL-1β mRNA (Minami et al. 1992; Liu et al. 1993; Buttini et al. 1994; Yabuuchi et al. 1994; Sairanen et al. 1997) and protein (Friedlander et al. 1997b; Sairanen et al. 1997; Zhang et al. 1998; Davies et al. 1999; Pearson et al. 1999; Skifter et al. 2002) expression is increased in brains of rodents following cerebral ischemia. The expression of IL-1β mRNA occurs in a time-dependent manner peaking anywhere from three (Minami et al. 1992; Buttini et al. 1994) to 12 h (Liu et al. 1993) depending on the ischemic insult of choice. Measurements of protein content immunocytochemically or by immunoassay indicate that IL-1β is produced early after occlusion, as well as throughout the later stages corresponding to the timing of the evolution of infarct (Davies et al. 1999; Skifter et al. 2002). Additionally, an up-regulation of IL-1RI can be observed in cortex, hippocampus, and striatum following cerebral ischemia in rats (Sairanen et al. 1997; Wang et al. 1997b). More importantly, this injury-induced increase in IL-1β and/or IL-1RI levels contributes to the neuronal cell death that occurs subsequent to cerebral ischemia (Relton and Rothwell 1992; Martin et al. 1994; Betz et al. 1995; Garcia et al. 1995; Toulmond and Rothwell 1995; Yamasaki et al. 1995; Relton et al. 1996; Friedlander et al. 1997b; Loddick et al. 1997; Boutin et al. 2001; Mizushima et al. 2002); for review, see also Rothwell and Relton (1993); Rothwell and Strijbos (1995); Rothwell et al. (1997); Loddick et al. (1998); Rothwell and Luheshi (2000)]. For instance, administration of either an IL-1β neutralizing antibody (Yamasaki et al. 1995) or IL-1ra (pharmacologically or genetically) markedly reduces subsequent cerebral ischemic damage (Relton and Rothwell 1992; Martin et al. 1994; Betz et al. 1995; Loddick and Rothwell 1996; Yang et al. 1997, 1998a, 1999b; Mulcahy et al. 2003). Animals deficient in ICE, the enzyme necessary for processing and activation of IL-1β, also show diminished infarct volumes along with a concomitant reduction in IL-1β levels (Hara et al. 1997; Schielke et al. 1998; Liu et al. 1999b). Finally, in mice lacking both IL-1α and IL-1β (but not either alone), brain injury after middle cerebral artery occlusion (Boutin et al. 2001; Ohtaki et al. 2003) or transient cardiac arrest (Mizushima et al. 2002) is markedly reduced. One might expect to find no change in the susceptibility to cerebral ischemic injury in IL-1α null mutants as the IL-1β gene is still expressed. However, the lack of effect in the IL-1β null mutants is somewhat perplexing given that no compensatory change in IL-1α expression was detected. Boutin and colleagues surmise that deletion of IL-1β results in compensatory changes in other aspects of the IL-1 system, although they were unable to definitely determine exactly what that change could be (Boutin et al. 2001). Nevertheless, it appears that the effects of chronic inhibition of IL-1β through gene deletion differ from acute inhibition via immunoneutralization (Yamasaki et al. 1995) or addition of IL-1ra (Relton and Rothwell 1992; Martin et al. 1994; Yang et al. 1999b). Still, consistent with a deleterious role for IL-1β, intraventricular injection of recombinant IL-1β, while not toxic alone, increases neuronal injury after MCAO in rat (Yamasaki et al. 1995). Further, immunoneutralization of endogenous IL-1ra markedly enhances ischemic damage (Loddick et al. 1997), indicating that IL-1ra plays a role in keeping endogenous IL-1β in check. A recent study demonstrated that loss of IL-1RI signaling was neuroprotective in a hypoxia-ischemia model (common carotid artery ligation coupled with hypoxia) (Basu et al. 2005) with an associated decrease in cytotoxic as well as vasogenic edema (Lazovic et al. 2005). In agreement, we recently showed that IL-1RI null mutant mice are less susceptible than wild-type control mice to focal cerebral ischemic damage induced by reversible MCAO (Fogal et al. 2007). However, a study that utilized the IL-1RI null mutants and the standard monofilament model of MCAO found negative results (Touzani et al. 2002). The rather short time of occlusion (30 min), which led to a comparably mild ischemic infarct, may not have activated the IL-1 pathway. Additionally, assessment of injury at a time point when injury might still be progressing may also explain the negative results. Finally, the concentration of IL-1β is significantly increased in the cerebrospinal fluid of stroke patients (Tarkowski et al. 1999; Gusev and Skvortsova 2003) and positive results of a prospective Phase II placebo-controlled study of recombinant human (rh)IL-1ra in patients with acute stroke have been published; the treatment was well tolerated and clinical outcomes at three months in the rhIL-1ra-treated patients (constant i.v. infusion for 72 h) was better than placebo-treated patients (Emsley et al. 2005). Thus, the totality of experimental – and now human data – provide compelling evidence that IL-1β is a contributing factor in brain injury that follows cerebral ischemia.

Despite this, the cellular and biochemical pathway(s) by which IL-1β contributes to neuronal cell death are poorly defined. Nevertheless several hypotheses have been proposed. First it was thought that the pyrogenic properties of IL-1 might explain its harmful effects (Rothwell 1991), since it is known that hyperthermia can increase brain damage following cerebral ischemia (Chopp et al. 1988; Maher and Hachinski 1993; Dietrich et al. 1996; Ginsberg and Busto 1998; Castillo et al. 1999). However, this theory has since been discounted (Relton and Rothwell 1992; Betz et al. 1995; Loddick et al. 1996; Loddick and Rothwell 1996; Stroemer and Rothwell 1998). Secondly, treatment of cultured human umbilical vein endothelial cells with IL-1β increases the production of the potent vasoconstrictor endothelin (Katabami et al. 1992), suggesting that IL-1β might adversely affect cerebral blood flow (Masaki 1989). However, interventions that prove protective, such as genetic expression of IL-1ra and genetic deletion of ICE or IL-1RI, had no effect on MCAO-induced cerebral blood flow measured by Laser Doppler Flowmetry (LDF) or autoradiography (Betz et al. 1995, 1996; Fogal et al. 2007). Thirdly, increased infiltration of leukocytes due to induction of adhesion molecules on endothelial, as well as on resident brain, cells could underlie some of the deleterious effects of IL-1β, as inhibition of IL-1 signaling results in decreased intercellular adhesion molecule expression, decreased leukocyte infiltration and a significant reduction of infarct size in rat models of cerebral ischemia (Garcia et al. 1995; Yamasaki et al. 1995; Yang et al. 1999a). Whether this is causal or coincidental remains to be determined. It should also be noted that IL-1β induces production of several factors known to participate in the pathology of cerebral ischemia, including other pro-inflammatory cytokines (e.g., IL-6, TNFα, IFN, IL-8) (Benveniste et al. 1990; Kasahara et al. 1991; Norris et al. 1994; Dinarello 2002), extracellular proteases (Thornton et al. 2006), phospholipase A2 (PLA2) (Hartung et al. 1989; Lin et al. 1992; Schalkwijk et al. 1993; Angel et al. 1994; Xue et al. 1995), cyclooxygenase-2 (O’Banion et al. 1996; Serou et al. 1999), NOS-2 (Hewett et al. 1993; Lee et al. 1993; Murphy et al. 1993; Serou et al. 1999), and other oxygen free radicals (Murray et al. 1999), indicating that it could be provoking injury via numerous cellular and biochemical pathways.

Of direct relevance to this review, changes in excitatory neurotransmission in response to IL-1β have been the focus of many studies. Indeed as mentioned above, NMDA-induced intracellular Ca2+ levels and subsequent neuronal cell death are increased in rat hippocampal cultures following IL-1β treatment (Viviani et al. 2003). Whether IL-1β could modify glutamate release was tested by Allan and colleagues, who found that addition of recombinant IL-1β had no significant effect on the KCl-evoked glutamate efflux from or calcium entry into striatal synaptosomes, indicating that its actions are unlikely to be pre-synaptic (Allan et al. 1998). Recently, we presented evidence for a novel mechanism by which IL-1β causes neuronal injury following hypoxic-ischemic insults: IL-1β-facilitated enhancement of glutamate excitotoxicity via increased system xc function (Fogal et al. 2007).

While the role of system xc activity in vivo remains to be confirmed, it should be noted that the same system xc antagonist (LY367385) used in our in vitro study (Fogal et al. 2007) is protective in animal models of cerebral ischemia (Moroni et al. 2002), although in the latter study the protective effect was attributed to an inhibition of metabotropic glutamate receptor (mGluR)1 signaling. Yet curiously, compared to their wild-type controls, neuronal injury following MCAO is not reduced in mGluR1-deficient mice (Ferraguti et al. 1997). Thus, the idea that inhibition of system xc might underlie the protection of the so-called mGluR1 antagonist in the aforementioned study deserves further attention. Nevertheless, why increase system xc if only to cause injury? The well-characterized role of this antiporter is to provide cystine for the production of the major cellular antioxidant glutathione (Meister and Anderson 1983; Bannai and Tateishi 1986; Deneke and Fanburg 1989; Dringen 2000). Hence, it is intriguing to speculate that IL-1β is released as a protective mechanism to up-regulate cystine transport (i.e., glutathione levels) in order to thwart excitotoxicity-mediated oxidative stress. In the same vein, glutathione S-transferase omega 1, one of the enzymes that catalyzes the conjugation of reduced glutathione with electrophilic substrates, has been demonstrated to increase post-translational processing of IL-1β (Laliberte et al. 2003), suggesting that glutathione expenditure can likewise increase mature IL-1β secretion. Indeed, there is close correlation between treatments that induce oxidant stress and those which induce system xc (Dun et al. 2006; Sakakura et al. 2007). While overall this potential general mechanism may be beneficial in most parts of the body, the associated increase in glutamate export could trigger neuronal cell death in an already impaired CNS.

Traumatic brain injury

Experimental traumatic brain injury (TBI) – induced by corticectomy, weight-drop, or fluid percussion – is associated with both a rapid and prolonged up-regulation of IL-1β (Nieto-Sampedro and Berman 1987; Woodroofe et al. 1991; Taupin et al. 1993; Fan et al. 1995; Herx et al. 2000; Kinoshita et al. 2002; Zhu et al. 2004; Lu et al. 2005; Kamm et al. 2006). Up-regulation of IL-1β has also been reported in the CSF (Morganti-Kossman et al. 1997; Shiozaki et al. 2005) and brain (Holmin and Hojeberg 2004) of humans following TBI. Since TBI can cause neurological deficits through direct mechanical disruption of neuronal pathways as well as through secondary mechanisms that develop over a period of hours to days following the primary insult (Faden and Salzman 1992; Faden 1993; McIntosh 1994), it has been suggested that the prolonged expression contributes to injury progression (Kamm et al. 2006). In support of this theory, intracerebroventricular administration of recombinant IL-1ra at time of injury or up to 48 h after experimental TBI in rodents decreases neuronal injury and improves functional outcome (Toulmond and Rothwell 1995; Jones et al. 2005). Additionally, mice genetically engineered to over-express IL-1ra show less histological injury and improved functional outcome following experimental TBI as compared to control animals (Tehranian et al. 2002). Finally, intraventricular administration of an IL-1β-neutralizing antibody prior to induction of TBI in rats significantly reduces neuronal loss (Lu et al. 2005). The main source of IL-1β following TBI appears to be microglia (Herx et al. 2000).

The mechanism by which IL-1β contributes to injury in the setting of TBI has not been extensively studied. Administration of an IL-1β-neutralizing antibody following cortical stab wound injury is associated with a decrease in astrocytic intercellular adhesion molecule expression-1 (Shibayama et al. 1996), possibly resulting in decreased CNS infiltration of leukocytes. Additionally, intracerebroventricular IL-1ra administration at the time of TBI initiation significantly reduces the number of NOS-2 positive cells (Jones et al. 2005). TBI is associated with increased [glutamate]e, excitotoxicity (Endres et al. 1989; McIntosh et al. 1989; Katayama et al. 1990), and oxidative stress (Hall et al. 1993; Smith et al. 1994; Pratico et al. 2002). As in cerebral ischemia, this could represent another mechanism by which IL-1β up-regulation occurs and contributes to injury in the setting of TBI. However, this awaits experimental confirmation as no study has assessed whether NMDA receptor antagonism or administration of antioxidants affect IL-1β induction in the setting of TBI. While a role for system xc in traumatic brain injury has not yet been investigated it is interesting to note that carboxyphenylglycines, inhibitors of both mGluR1 and system xc-, reduce neuronal cell death following mechanical injury in vitro (Mukhin et al. 1996; Faden et al. 2001). A role for mGluR1 signaling in this injury setting has been confirmed using antisense strategy (Mukhin et al. 1996; Faden et al. 2001); however, additional protective effects of these compounds via inhibition of system xc cannot be ruled out.

Spinal cord injury

Several lines of evidence indicate that increased expression of IL-1β contributes to tissue damage following spinal cord injury (SCI). IL-1β mRNA and protein are increased at the lesion site as early as 1 h following SCI in rats (Wang et al. 1997a) or mice (Bartholdi and Schwab 1997). An up-regulation of IL-1β protein levels has also been reported within the same time frame in human spinal cord after contusion injury (Yang et al. 2004). Experimentally, local administration of recombinant IL-1ra via an osmotic pump for 72 h after contusion-induced injury, significantly decreases the cell death at the lesion site (Nesic et al. 2001), indicating that the increases in IL-1β levels contribute to the development of injury. Just as for cerebral ischemia and TBI, the main source of IL-1β following SCI appears to be microglial cells (Yang et al. 2004, 2005).

Is there a link between excitotoxicity, oxidative stress, and IL-1β in the setting of SCI? While it remains to be determined definitely, elevated [glutamate]e occurs after injury (Panter et al. 1990) to concentrations known to be toxic to spinal cord neurons (Regan and Choi 1991; Liu et al. 1999a; Xu et al. 2005). Further, treatment with NMDA receptor antagonists improves functional outcome in rat SCI models (Hao et al. 1992; Panter and Faden 1992; Yanase et al. 1995). Glutamate toxicity also contributes to motor neuron loss in an in vitro model of traumatic SCI, and an increase in expression of antioxidant enzymes is protective in this same model (Liu et al. 2007). Since microglial production of IL-1β can be inhibited by the antioxidants trolox or NAC (Min et al. 2003) and the mGluR1/system xc blocker 4-carboxyphenylglycine protects from injury in an in vitro SCI model (Agrawal et al. 1998), a more detailed investigation of the relationship between excitotoxicity, oxidative stress, and IL-1β may reveal their association under the conditions of SCI.

Chronic neurodegenerative disorders

Alzheimer’s disease

Elevated levels of IL-1 have been found in postmortem brain tissue from (Griffin et al. 1989), as well as in CSF of (Cacabelos et al. 1991) Alzheimer’s disease patients. A correlation between the distribution of IL-1 expressing microglia and amyloid plaque formation also has been described (Griffin et al. 1989; Sheng et al. 1995, 1998b). While Vandenabeele and colleagues proposed that the amyloid plaque formation in the brain – characteristic for Alzheimer’s disease (AD) – may be caused by an IL-1/IL-6-mediated inflammatory response (Vandenabeele and Fiers 1991), the question remains as to whether the increase in IL-1 in the setting of AD is harmful or beneficial?

Human IL-1 gene polymorphisms, which are associated with increased IL-1 production, have been documented to increase the relative risk for AD and/or promote earlier disease onset (Grimaldi et al. 2000; Mrak and Griffin 2000; Nicoll et al. 2000; Licastro et al. 2004), suggesting that increased IL-1β expression is indeed harmful. In seeming support, IL-1 can increase expression of β-amyloid precursor protein (βAPP) (Goldgaber et al. 1989; Yang et al. 1998b; Ma et al. 2005; Griffin et al. 2006), whose cleavage product amyloid β (Aβ) comprises the primary component of amyloid plaques. Expression of acetylcholinesterase (AChE) can be enhanced in PC12 cells by IL-1 (Li et al. 2000) and AChE inhibitors improve early memory deficits in AD patients (Giacobini 2003; Terry and Buccafusco 2003; Small 2004). Along the same line, IL-1β inhibits ACh synthesis in pituitary corticotropic AtT20 cells (Carmeliet et al. 1989). Hence, IL-1 may contribute to the histological and functional pathology of AD by enhancing Aβ production and decreasing ACh levels via a number of different pathways. Finally, a recent study suggests that IL-1β interferes with intrinsic neurotrophic support by interrupting the bone-derived neurotrophic factor signaling cascade (Tong et al. 2008) – a mechanism that has been linked to the progression of AD (Chao et al. 2006).

With particular relevance to this review, oxidative stress and glutamate toxicity either contribute or perhaps even cause AD. In this respect, increased oxidative DNA damage has been reported (Mecocci et al. 1994; Lyras et al. 1997) and markers of oxidative stress have been localized to neurofibrillary tangles and amyloid plaques in AD brain (Good et al. 1996; Smith et al. 1996). Additionally, human cortical cell cultures treated with Aβ peptide are more vulnerable to glutamate excitotoxicity (Mattson et al. 1992). Memantine, an NMDA-receptor antagonist, protects against neurodegeneration induced by hippocampal injection of Aβ proteins in rats (Miguel-Hidalgo et al. 2002) and, more importantly, improves the cognitive deficits in Alzheimer’s disease patients (Reisberg et al. 2003, 2006), providing further evidence that an alteration in glutamatergic neurotransmission contributes to the disease progression. Interestingly, increased glutamate export via system xc has been suggested to contribute to excitotoxic neuronal cell death in AD (Barger and Basile 2001; Qin et al. 2006). Specifically, Barger and colleagues show that soluble APP increases glutamate release via system xc in microglia. Whether this occurs via an IL-1β-dependent mechanism was not explored but would be of interest given the link between IL-1 and APP gene expression (Goldgaber et al. 1989; Yang et al. 1998b; Ma et al. 2005; Griffin et al. 2006).

It is important to stress the potential benefit of an increase in system xc function, since an increase in the production of the antioxidant glutathione could protect from pathogenic components of AD. In fact, oxidative damage is one of the earliest changes in AD brain (Nunomura et al. 2001). Additionally, Aβ can act as an antioxidant (Cuajungco et al. 2000). As such, it has been proposed that its deposition may be a compensatory response to oxidative damage (Smith et al. 2000a; Nunomura et al. 2001; Rottkamp et al. 2002; Smith et al. 2002; Lee et al. 2004; Zhu et al. 2007). Hence, it is intriguing to speculate that mechanisms put in place to protect from oxidative stress might, under certain conditions, contribute to AD pathology. Importantly, the beneficial effects of an IL-1β-mediated inflammatory response in the hippocampus have been recently demonstrated in a mouse model of AD (Shaftel et al. 2007b). Sustained over-expression of human IL-1β in the hippocampus of the APPswe/PS1ΔE9 mouse resulted in decreased amyloid plaque formation, despite a robust neuroinflammatory response (Shaftel et al. 2007b), highlighting the complex and potentially bidirectional biologic effects of IL-1β in CNS tissue responses.

HIV-associated Dementia

HIV-associated dementia (HAD) is a common neurological disorder associated with HIV-infection. Clinically, HAD is characterized by disabling cognitive impairment, including poor concentration and memory impairment; motor dysfunction, such as loss of fine motor control, poor balance, tremors, speech problems; and behavioral changes including apathy and lethargy (Rothenhausler 2006; Ances and Ellis 2007). The exact mechanisms by which HIV causes HAD are not completely understood. Since no evidence for neuronal HIV-infection exists (Simpson and Tagliati 1994), it has been suggested that HIV-infected microglia and astrocytes indirectly cause neuronal injury and death via release of neurotoxic factors, including cytokines, one of which is IL-1β (Nottet and Gendelman 1995; Kaul et al. 2001). Interestingly, the neurotoxicity of gp120, a glycoprotein exposed on the surface of the HIV envelope, when injected intracerebroventricularly is prevented by concomitant injection of IL-1ra (Bagetta et al. 1999). Importantly, IL-1β mRNA levels are also increased in postmortem brain tissue from HIV-infected patients diagnosed with HAD as compared to non-demented HIV-infected patients (Zhao et al. 2001), substantiating a role for IL-1β in the pathogenesis of HAD. The mechanism(s) by which IL-1β signaling might contribute to the progression of neuronal injury in HAD are incompletely understood. Recently, Viviani and colleagues showed that treatment of rat hippocampal neuron-glia cultures with gp120 for 24 h results in increased phosphorylation of the NR2B subunit of the NMDA receptor resulting in subsequent calcium dysregulation in neurons (Viviani et al. 2006). Like the neurotoxicity induced in vivo, these effects of gp120 were inhibited by IL-1ra (Viviani et al. 2006). Additionally, gp120 neurotoxicity in vivo (Toggas et al. 1996) and in vitro (Lipton 1992) is decreased by NMDA receptor antagonism, providing a potential link between IL-1β and excitotoxicity. Additional evidence links IL-1β to oxidative stress. Exposure of microglia to gp120 induces both ROS and IL-1β formation. While an anti-IL-1β neutralizing antibody protects from gp120-induced neuronal injury, the antioxidant trolox prevents both increased IL-1β release and neurodegeneration, suggesting ROS to be the initiator (Viviani et al. 2001). Additionally, the neurotoxic effects of gp120 depend on the presence of glia (astrocytes and/or microglia) (Viviani et al. 2001), similar to the IL-1β-mediated effect on system xc reported by us (Fogal et al. 2007). Hence, it is intriguing to speculate that in addition to direct effects of IL-1β on glutamate receptor function (Viviani et al. 2006), changes in systems that affect extracellular [glutamate]e may also contribute.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease, marked by the gradual degeneration of motor neurons in the brain, brainstem and spinal cord (Lowe and Leigh 2002). To study the mechanism(s) involved, transgenic mice expressing a mutant form of cupper/zinc superoxide dismutase (SOD) are often used as a model, since mutations in the SOD-1 gene are associated with the inherited form of ALS in humans (Bendotti and Carri 2004). In animals this mutation results in an age-dependent progressive degeneration of motor neurons similar to human ALS (Gurney et al. 1994). While the role of IL-1β in ALS pathology is not well studied, it is important to note that SOD-1 down-regulation in PC12 cells results in increased IL-1β expression and cell death, the latter of which is inhibited by IL-1ra, an anti-IL-1β neutralizing antibody, or by inhibitors of ICE (Troy et al. 1996). Furthermore, mice expressing mutant forms of SOD-1 and ICE survive significantly longer compared to their SOD-1-mutant littermates. Since disease onset does not differ between double mutants and control animals, these findings suggest a role for IL-1β in disease progression (Friedlander et al. 1997a). Additionally, oxidative stress increases ICE activity in a neuroblastoma cell line (N2a cells) harboring an SOD-1 mutation, which is accompanied by cleavage and secretion of IL-1β (Pasinelli et al. 1998). Hence, it is intriguing to speculate that IL-1β is released as a protective mechanism to up-regulate system xc in an effort to increase glutathione production to protect against oxidative stress. Since decreased glutamate transporter function also appears to be a component of ALS (Rothstein et al. 1992; Shaw et al. 1994; Fray et al. 1998; Sasaki et al. 2000), it would not be surprising that this potential beneficial mechanism becomes harmful by contributing to an increase in [glutamate]e. Indeed, levels of [glutamate]e are elevated in the cortex of mutant SOD-1 mice (Alexander et al. 2000) as well as in the medulla (Pioro et al. 1999) and CSF (Rothstein et al. 1990; Shaw et al. 1995) of ALS patients. Additionally, CSF from ALS patients is toxic to cortical neurons in culture, an effect blocked by glutamate receptor antagonism (Heath and Shaw 2002) Interestingly, reduction of [glutamate]e is the only therapeutic strategy that demonstrates benefit by slowing disease progression in ALS patients (McGeer and McGeer 2005). Hence, a more detailed investigation of the relationship between oxidative stress, IL-1β and excitotoxicity may reveal an intimate connection in the setting of ALS.

Multiple sclerosis

Multiple sclerosis (MS) is best considered a chronic, inflammatory demyelinating disease. However, it is now accepted that neurodegenerative processes, including axonal loss occur (McFarland and Martin 2007). With respect to IL-1β, elevated levels are observed in the CSF of rats in various stages of chronic relapsing experimental allergic encephalomyelitis (Diab et al. 1997) and of patients suffering from MS (Maimone et al. 1993; Hermans et al. 1997). IL-1 signaling appears to play a role in the initial inflammatory response by activating the T-cell type critical for disease development in animal models of MS (McFarland and Martin 2007). However, considering the evidence presented thus far, an effect on neuronal and/or oligodendrocyte survival in MS should not be neglected. Certainly, markers of oxidative stress are increased in MS lesions (Cross et al. 1998; Oleszak et al. 1998; Liu et al. 2001) and, as mentioned, oxidative stress is an inducer of IL-1β expression (Troy et al. 1996; Viviani et al. 2001; Min et al. 2003; Brabers and Nottet 2006). Additionally, excitotoxicity is also involved (Matute et al. 2007; Gonsette 2008). Takahashi and colleagues show that IL-1β kills oligodendrocytes via a glutamate receptor-dependent mechanism when cells are co-cultured with astrocytes (Takahashi et al. 2003). While it is hypothesized that decreased system XAG function is the underlying mechanism, a concomitant increase in system xc function should also be considered in light of our recent findings (Fogal et al. 2007) and those of Domercq and colleagues, who demonstrate that activated microglia release glutamate via system xc in quantities sufficient to injure oligodendrocytes in culture (Domercq et al. 2007). Of relevance to either finding, [glutamate]e is increased in the CSF of MS patients (Stover et al. 1997) and inhibition of glutamate receptor signaling decreases the neurological deficits as well as the axonal and oligodendroglial damage associated with experimental allergic encephalomyelitis in mice (Wallstrom et al. 1996; Pitt et al. 2000; Smith et al. 2000b; Werner et al. 2000). So here too the hypothesis that IL-1β mediates the bridge between inflammation and excitotoxicity is particularly pertinent.

Parkinson’s disease

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder best characterized by substantia nigral dopaminergic neuronal cell loss. While the exact cause(s) of this destruction is (are) not yet fully understood, compelling evidence indicates that oxidative stress contributes to the pathogenesis of PD [for review, see Jenner and Olanow (2006)]. At the cellular level, both human and animal studies point to a deficiency in mitochondrial energy metabolism leading to increased free-radical formation (Johannessen et al. 1985; Nicklas et al. 1985; Tipton and Singer 1993; Parker and Swerdlow 1998; Lotharius et al. 1999). Could this oxidative stress mechanistically link to alterations in IL-1β levels? While this specific question has not been experimentally tested, IL-1 levels have been found to be increased in postmortem striata taken from PD patients (Mogi et al. 1994) and IL-1 gene polymorphism – associated with increased IL-1 production – are more frequent in Parkinson’s disease patients than control patients (Mattila et al. 2002; Schulte et al. 2002; Nishimura et al. 2005; Wahner et al. 2007). It is interesting to note that a reduction in the concentration of glutathione is observed in brains of PD patients (Perry and Yong 1986; Sian et al. 1994). The hypothesis that this change could contribute to the development of PD (Bannon et al. 1984; Chinta et al. 2007) is supported by a recent study showing that NAC treatment restores glutathione levels and ameliorates motor dysfunction in the MPTP model of PD (Aoyama et al. 2008). In light of our recent findings (Fogal et al. 2007), it is again intriguing to speculate that IL-1 may be up-regulated to counteract glutathione depletion via increased system xc activity. Since decreased glutamate transporter function may also contribute to the development of PD (Dervan et al. 2004; Holmer et al. 2005), this potentially protective response could turn detrimental. Additionally, changes in GSTO-1, the enzyme that can contribute to regulation of both IL-1β and glutathione levels, have been associated with an earlier onset of PD (Li et al. 2006), perhaps providing another piece of evidence in support of the double hit hypothesis.

Interestingly, in the MPTP mouse model of Parkinson’s disease, treatment with minocycline prevents activation of microglia, IL-1β release, and dopaminergic neuronal cell death (Wu et al. 2002), suggesting a possible role for IL-1β in neuronal cell death. Direct support for this supposition was provided in two studies. Ferrari and colleagues demonstrate that chronic over-expression of IL-1β in the substantia nigra of rats results in dopaminergic cell death (Ferrari et al. 2006) and mice deficient in ICE are less susceptible to MPTP toxicity in vivo (Klevenyi et al. 1999). Given the evidence for a role of glutamate toxicity in several animal models of PD (Sonsalla et al. 1989, 1991; Turski et al. 1991; Storey et al. 1992; Srivastava et al. 1993; Beal 1998; Sonsalla et al. 1998) and the additional association between IL-1β and excitotoxicity, it would be interesting to know whether the IL-1β-mediated enhancement in injury seen in this model is associated with changes in [glutamate]e and/or could be prevented by glutamate receptor antagonism. The latter experiment might not be feasible given the long-term nature of the studies, although the underlying hypothesis should not be discounted.

Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that is caused by a trinucleotide repeat expansion in the Huntingtin (htt) gene. The expansion results in the production of an altered form of htt protein (mutant Htt, or mHTT), which results in neuronal cell death in selected areas of the brain (Dunnett and Rosser 2004). Surprisingly, a role for IL-1β in the pathology of Huntington’s disease has not been considered even though IL-1β levels are increased in a mouse HD model, as well as in the cortex of HD patients (Ona et al. 1999). Additionally, when ICE function is inhibited in the brain of HD mice, the progression of motor dysfunction is delayed (Ona et al. 1999). Because ICE is also responsible for cleavage of htt (Wellington et al. 1998), the effect of ICE inhibition by those in the HD field has been attributed to this mechanism and a possible role for IL-1β has been neglected.

Both oxidative stress and excitotoxicity have been implicated in HD pathology (Fan and Raymond 2007). With respect to the former, postmortem human brains (Montine et al. 1999; Polidori et al. 1999) and brains of transgenic HD mouse show elevated levels of oxidative damage products, such as malondialdehyde, 8-hydroxyguanosine, and 3-nitrotyrosine (Perez-Severiano et al. 2000; Bogdanov et al. 2001; Perez-Severiano et al. 2004). And, increased production of ROS, via mitochondrial complex II blockade, contributes to the neuropathology in the 3-nitropropionic acid (3-NP) model of HD (Butterfield et al. 2001; Tunez et al. 2004). With respect to the latter, the NMDA receptor antagonist, MK-801, inhibits 3-NP neurotoxicity in vitro (Fink et al. 1996) and in vivo (Beal et al. 1993; Kim et al. 2000). Furthermore, striatal neurons derived from the R6/2 mouse model of HD have enhanced NMDA receptor currents and calcium influx (Cepeda et al. 2001). Finally, reduced rodent glutamate transporter subtype I mRNA expression in R6/2 mouse brain (Behrens et al. 2002) and in postmortem human brain taken from HD patients (Arzberger et al. 1997) has been reported, suggesting that an alteration in glutamate transport may also contribute. Taken together, these data suggest that an overall enhanced susceptibility to excitotoxicity may be a contributory factor to disease pathology. Interestingly, an age-dependent increase in glutathione levels in R6/2 mice has been reported (Fox et al. 2004). Whether the increased glutathione production involves enhanced system xc activity, with the associated efflux of glutamate, remains to be determined. In light of the intricate relationship between IL-1β, oxidative stress, and excitotoxicity, as detailed in this review, exploring the role of IL-1β in HD is worth consideration.

Conclusion

  1. Top of page
  2. Abstract
  3. The interleukin-1 family
  4. Interleukin-1 in the brain
  5. Interleukin-1β and neuronal injury
  6. Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders
  7. Conclusion
  8. Acknowledgments
  9. References

A vast number of studies, detailed herein, provide evidence for a role of IL-1β in the pathology of a number of acute and chronic neurological disorders. Additionally, we discuss evidence that leads us to propose IL-1β as the missing mechanistic link between a potential beneficial inflammatory response and detrimental glutamate excitotoxicity. While the initial trigger for acute injury or chronic disease may differ between neurological disorders, the resulting pathology may involve overlapping, if not identical, mechanisms. As such, we propose that a better understanding of the interplay between IL-1β, oxidative stress, and glutamate excitotoxicity will facilitate the development of promising therapeutics in the field of CNS disorders.

References

  1. Top of page
  2. Abstract
  3. The interleukin-1 family
  4. Interleukin-1 in the brain
  5. Interleukin-1β and neuronal injury
  6. Re-examination of the relationship between interleukin-1, excitotoxicity, and oxidative stress in neurological disorders
  7. Conclusion
  8. Acknowledgments
  9. References
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