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Keywords:

  • alarmins;
  • biomarkers;
  • brain distress;
  • human biological fluids;
  • S100B protein

Abstract

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

J. Neurochem. (2012) 120, 644–659.

Abstract

S100B is a calcium-binding protein concentrated in glial cells, although it has also been detected in definite extra-neural cell types. Its biological role is still debated. When secreted, S100B is believed to have paracrine/autocrine trophic effects at physiological concentrations, but toxic effects at higher concentrations. Elevated S100B levels in biological fluids (CSF, blood, urine, saliva, amniotic fluid) are thus regarded as a biomarker of pathological conditions, including perinatal brain distress, acute brain injury, brain tumors, neuroinflammatory/neurodegenerative disorders, psychiatric disorders. In the majority of these conditions, high S100B levels offer an indicator of cell damage when standard diagnostic procedures are still silent. The key question remains as to whether S100B is merely leaked from injured cells or is released in concomitance with both physiological and pathological conditions, participating at high concentrations in the events leading to cell injury. In this respect, S100B levels in biological fluids have been shown to increase in physiological conditions characterized by stressful physical and mental activity, suggesting that it may be physiologically regulated and raised during conditions of stress, with a putatively active role. This possibility makes this protein a candidate not only for a biomarker but also for a potential therapeutic target.

Abbreviations used:
AD

Alzheimer’s disease

ALS

amyotrophic lateral sclerosis

DAMPs

damage-associated molecular pattern molecules

IVH

intra-ventricular haemorrhage

MS

multiple sclerosis

PD

Parkinson’s disease

RAGE

advanced glycation end product

The S100B protein was identified in the mid-1960s as a protein fraction which – on the basis of chromatographic and electrophoretic methods available at that time – was detectable in the brain but not in non-neural extracts, and was named S100 because of its solubility in a 100% saturated solution with ammonium sulphate (Moore 1965). At present, owing to the discovery of a series of proteins exhibiting structural similarities, the term S100 is used to embrace a multigenic family of mostly dimeric calcium-binding proteins comprising more than 20 members with different degrees of homology to each other at the amino acid level, and representing the largest subgroup within the EF-hand superfamily. The genes encoding the majority of human S100 proteins are organized in a cluster within the chromosomal region 1q21, while some genes coding individual S100 proteins are located in other chromosomal regions, including 21q22 where, in particular, the gene for the S100B protein is located. Each monomer is approximately 10–12 kDa and is characterized by two calcium-binding regions, each comprising two alpha helices with an intervening calcium-binding loop forming a conserved pentagonal arrangement around the calcium ion (EF-hand motif).The binding of calcium to EF-hand domains triggers conformational changes that allow interactions with other proteins, so that S100 proteins are thought to be calcium sensor proteins that modulate biological activity via calcium binding. In addition, some S100 members have been shown to bind zinc and/or copper, suggesting the possibility that in some cases their biological activity might be regulated by these metals. Structural plasticity occurring at the quaternary level, where several S100 proteins self-assemble into multiple oligomeric states, has also been proposed to be functionally relevant. S100 proteins are currently believed to play a variety of biological roles, including the regulation of protein phoshorylation, cell growth and motility, cell cycle, transcription, differentiation and cell survival, acting intracellularly or extracellularly. These structural and biological features of the S100 protein family have already been treated by exhaustive and valuable reviews (Donato 2001; Fritz et al. 2010; Leclerc and Heizmann 2011; Thulin et al. 2011). Interestingly, the S100 proteins are highly conserved in amino acid composition among vertebrate species, suggesting that they may have crucially conserved biological roles (Fanòet al. 1995), and an S100-like protein has even been immunologically detected in planarians (Michetti and Cocchia 1982).

In particular S100B, the beta–beta homodimer, constitutes the bulk of the fraction originally isolated from brain extracts and was regarded for almost two decades as specific to the nervous system. It was subsequently demonstrated that in fact the protein is not restricted to nervous tissue (Cocchia et al. 1981). Since then, the cell distribution of S100B has been extensively studied in mammalian tissues, including human tissues. In the nervous system, S100B is concentrated in astrocytes and other glial cell types, such as oligodendrocytes, Schwann cells, ependymal cells, enteric glial cells, retinal Muller cells, while its presence in definite neuron subpopulations has also been reported (Ludwin et al. 1976; Brockes et al. 1979; Ferri et al. 1982; Didier et al. 1986; Rickmann and Wolff 1995; Yang et al. 1995). In non-neural tissues, the protein is widely distributed in definite cell types, including melanocytes, Langerhans cells, chondrocytes, dendritic cells in lymphoid organs, adrenal medulla satellite cells, Leydig cells, skeletal muscle satellite cells (Cocchia et al. 1981, 1983; Stefansson et al. 1982; Lauriola et al. 1985; Michetti et al. 1985; Tubaro et al. 2010), while adipose tissue constitutes a site of concentration comparable to nervous tissue (Michetti et al. 1983).

Many hypotheses have been formulated concerning the biological role(s) of S100B within the cell populations that contain it, but its intracellular function has not yet been clearly elucidated. The protein has been reported to interact with the cytoskeleton (Baudier and Cole 1988; Donato 1988; Skripnikova and Gusev 1989; Mbele et al. 2002), to play significant roles in cell proliferation, survival and differentiation (Baudier et al. 1992; Millward et al. 1998; Arcuri et al. 2005; Raponi et al. 2007; Saito et al. 2007), to participate in the regulation of cellular calcium homeostasis (Xiong et al. 2000; Gentil et al. 2001Tsoporis et al. 2009) and to regulate some enzyme activities (Zimmer and Van Eldik 1986; Heierhorst et al. 1996; Pozdnyakoz et al. 1997; Brozzi et al. 2009). The nature of the above findings does not appear to converge towards a univocal intracellular function of S100B; rather, as a calcium sensor protein, S100B appears to intervene in a variety of intracellular activities by interacting with different proteins after its calcium-dependent conformational modification.

The S100B protein was first detected in extracellular biological fluids – in particular in the CSF – of multiple sclerosis (MS) patients in concomitance with the acute phase of exacerbation (Michetti et al. 1979). Its detection in biological fluids cast the protein as a candidate biomarker of active cell injury in the nervous system, when it was found in CSF of patients affected by a series of pathological conditions such as acute encephalomyelitis, amyotrophic lateral sclerosis (ALS) and intracranial tumors (Michetti et al. 1980). Since then, research on S100B as a biomarker of brain distress has been extended to other biological fluids besides CSF, such as peripheral blood (Kato et al. 1983), cord blood (Gazzolo et al. 2000), amniotic fluid (Gazzolo et al. 2001a), urine (Gazzolo et al. 2001b) and saliva (Gazzolo et al. 2005b). Originally, the rationale of these studies was based on the assumption that the detection of S100B in biological fluids was a consequence of its leakage from damaged cells. However, S100B has also been shown to be actively released by some cell types that contain it (Shashoua et al. 1984; Suzuki et al. 1984; Van Eldik and Zimmer 1987; Gerlach et al. 2006; Ellis et al. 2007). In this respect, growing evidence suggests that secreted S100B acts in either an autocrine, a paracrine or even an endocrine manner with concentration-dependent effects that are trophic (‘Jekyll side’) at what are thought to be physiological, nanomolar concentrations, but toxic (‘Hyde side’) at higher (micromolar) concentrations. In particular, low (nanomolar) concentrations of S100B have been reported to be able to promote neurite extension, protect neuron survival, and participate in the regulation of muscle development and regeneration (Kligman and Marshak 1985; Winningham-Major et al.1989; Bhattacharyya et al. 1992; Barger et al. 1995; Haglid et al. 1997; Iwasaki et al. 1997; Ahlemeyer et al. 2000; Sorci et al. 2003; Businaro et al. 2006; Kleindienst and Ross Bullock 2006); however, micromolar S100B has been shown to up-regulate inducible NOS, induce NO release in astrocytes and in microglia, up-regulate cyclooxygenase-2 expression in microglia and monocytes, induce NO-dependent death of astrocytes and neurons, increase the production of reactive oxygen species in neurons, and induce perturbation of lipid homeostasis and cell cycle arrest (Hu et al. 1996, 1997; Huttunen et al. 2000; Petrova et al. 2000; Adami et al. 2001; Esposito et al. 2008; Shanmugam et al. 2008; Bernardini et al. 2010; Bianchi et al. 2010). Extracellular S100B has been shown to trigger cellular signaling through interaction with the multiligand Receptor for Advanced Glycation End Product (RAGE) (Hofmann et al. 1999; Huttunen et al. 2000), which, however, appears not to be the sole S100B receptor (Riuzzi et al. 2011). A new scenario has thus been opened in which high concentrations of S100B may be regarded as an active factor participating in the cascade of events leading to cell injury, as well as – or rather than – being leaked from damaged cells, while its secretion at low (putatively physiological) concentrations is believed to have trophic effects. It seems relevant in this respect that S100B, in common with other S100 proteins, shares characteristics such as the interaction with RAGE, the non-canonical secretion modality that by-passes the classical Golgi route, and the ability to stimulate microglial migration (Foell et al. 2007; Sorci et al. 2010), with damage-associated molecular pattern molecules (DAMPs), or alarmins, endogenous molecules that are released during cellular injury and participate in the activation of pro-inflammatory pathways (for review, Chen and Nuñez 2010). A series of findings indicate that S100B can exert a proinflammatory role (Adami et al. 2001; Koppal et al. 2001; Lam et al. 2001; Valencia et al. 2004; Liu et al. 2005; Schmitt et al. 2007) while a role in the resolution of inflammatory processes has also been described for this protein (Sorci et al. 2011). With these considerations in mind, while valuable reviews essentially focusing on biological and/or definite physiopathological features of this protein have recently been published (Rothermundt et al. 2007; Donato et al. 2009; Steiner et al. 2011), the present review examines the principal circumstances in which altered concentrations of S100B have been observed in human biological fluids. The meaning of these findings for the diagnosis of neural and extra-neural pathological conditions, as well as for the possible interpretation of the role of S100B will also be examined.

S100B in perinatal medicine

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

Significant information has been acquired through assessments of S100B in the biological fluids of newborns at risk of brain damage in conditions such as asphyxia, intraventricular hemorrhage (IVH), post-hemorrhagic ventricular dilatation and hypoxia-ischemia following cardiac surgery (Sellman et al. 1992; Gazzolo et al. 1998; Blennow et al. 2001; Whitelaw et al. 2001). S100B was also recently used to monitor the impact of prenatal drug exposure (Gazzolo et al. 2002a, 2003b; Pawluski et al. 2009; Sannia et al. 2010). All the biological fluids in which the levels of S100B have been investigated to date have been found to be useful in perinatal medicine.

In the light of the earlier assumption that S100B is leaked primarily from damaged cells, the first fluid in which S100B was examined was CSF, owing to its anatomical and biochemical peculiarities. In preterm infants affected by perinatal hypoxia and post-hemorrhagic ventricular dilatation CSF S100B levels correlated with the extent of brain lesions and with long-term prognosis (Blennow et al. 2001; Whitelaw et al. 2001). Although data were promising, CSF was progressively abandoned in perinatal medicine, essentially on account of the stressful procedure involved in its collection.The evaluation of S100B was preferentially performed using amniotic fluid and cord/peripheral blood.

Elevated concentrations of S100B in amniotic fluid of anencephalic and/or neural tube defect fetuses were found to correlate with the occurrence of CNS malformations and damage (Sindic et al. 1984). Later, the presence of this protein was examined in the amniotic fluid of mono/biamniotic twins with the aim of exploring a physiological, and possibly neurotrophic, role for S100B during human development. Interestingly, an approximately double concentration of S100B was observed in physiological monoamniotic twin pregnancies compared with diamniotic or singleton pregnancies, hinting at the possibility that each fetus releases a physiologically defined amount of S100B (Gazzolo et al. 2003c). S100B has also been investigated as a diagnostic tool of fetal genetic syndromes of the CNS. In this respect, the concentration of S100B in amniotic fluid in trisomy 21-complicated pregnancies was approximately 1.5 times higher than in controls (Gazzolo et al. 2003a; Tort et al. 2004). These findings are not surprising, because the protein is known to be coded in the chromosomal region 21q22 (Allore et al. 1988), while the question remains concerning a pathogenic role of the protein. Investigation of S100B levels in amniotic fluid in the middle trimester indicated that the protein was a promising tool for the prediction of unexplained intrauterine death, with a sensitivity, specificity, and positive and negative predictive values of 100% (Florio et al. 2004). A possible involvement of the protein in the pathological mechanisms leading to fetal death might underlie this finding, and constitutes a promising field for future investigation. The origin of S100B in amniotic fluid is still being debated. Data on a possible placental origin, essentially based on immunohistochemical findings, are controversial (Gazzolo et al. 2002b; Marinoni et al. 2002; Wijnberger et al. 2002). Thus, the possibility that increased S100B protein derives from the CNS and/or non-nervous tissues has reasonably to be taken into consideration.

The fetal bloodstream has been widely investigated on account of its interesting properties such as low sampling stress and adequate sample volume collection (Gazzolo et al. 2000). This has been used to monitor: (i) increased S100B levels in intrauterine growth retarded fetuses (Gazzolo et al. 2002b); (ii) the effectiveness/side-effects of antenatal therapeutic strategies such as glucocorticoids or nitric oxide donors in high risk pregnancies (Gazzolo et al. 2002a, 2003b; Sannia et al. 2010), and anti-depressive drugs (Pawluski et al. 2009). Interestingly, overlapping S100B patterns have been shown in pregnancies during which mothers were exposed to alcohol or cocaine (Akbari et al. 1994; Tajuddin and Druse 1999; Eriksen et al. 2000).

The intriguing hypothesis was raised that the particular properties of S100B (low molecular weight) could lead to the protein crossing the placenta and being transported from the fetal to the maternal bloodstream. Thus, an extra aliquot of fetal S100B could be detectable in maternal blood when high levels of the protein are present in the fetus in concomitance with pathological conditions. In fact, high maternal blood S100B concentrations have been shown to be a reliable tool (sensitivity 100%; specificity 99.3%; positive and negative predictive values 100% and 93%, respectively) to identify newborns at risk of IVH in pregnancies complicated by intrauterine growth retarded fetuses (Gazzolo et al. 2006). These findings support the hypothesis that the monitoring of fetal well-being/stress by evaluating a fetus-derived biomarker in the maternal bloodstream may become possible.

The measurement of S100B levels in urine has also been used in perinatal medicine as a means to obtain a non-invasive diagnostic tool. Thus, urine S100B concentrations have been shown to be correlated with gestational age in healthy preterm and term newborns (Gazzolo et al. 2001c), and urine S100B concentrations at birth have been shown to be significantly higher in preterm newborns developing IVH and/or brain damage (Gazzolo et al. 2001b, 2003d; Liu et al. 2010). They have also been shown to be a valuable predictor of early neonatal death in preterm and full-term asphyxiated newborns (Gazzolo et al. 2005a, 2009).

Saliva offers the optimality criteria required for brain monitoring in newborns, as it can be collected with a simple and non-invasive procedure. Several studies have shown that in the third trimester of pregnancy S100B is not expressed in salivary glands (Lee et al. 1993; Huang et al. 1996; Humphrey and Williamson 2001), suggesting that the protein detected in saliva could derive from systemic circulation. Reference curves have been indicated for S100B in the perinatal period (Gazzolo et al. 2005b) to support the monitoring of infants with CNS diseases.

It is also noteworthy that S100B is present in human milk, at concentrations estimated to be 80/100 times higher than those detected in CSF, blood or urine. The concentration of the protein in human milk increases with milk maturation and is higher than that detected in milk of other species such as cow, goat, donkey or sheep, thus possibly suggesting a relationship between the milk S100B concentration, human development and species evolution (Gazzolo et al. 2003e, 2004; Galvano et al. 2009). The presence of S100B at very high concentrations in human milk may be related to its putative neurotrophic role, it being well known that different substances influencing infant growth (hormones, growth factors) are present in human milk (Amin et al. 2000); it is therefore tempting to speculate that this protein may have a nutritional role in maternal milk, including possible effects on trophism of the enteric nervous system (Li et al. 2011b). In addition, the evaluation of milk S100B promises to offer a new tool in the investigation of maternal physiopathological conditions, with a potential impact on the health of newborns.

S100B in acute brain injury, and more

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

S100B protein is detectable at high concentrations in CSF and serum both in brain trauma and in acute brain injury caused by cardiovascular disorders, in some cases also correlating with the size of the lesion as evaluated using radiological criteria (Persson et al. 1987; Aurell et al. 1991; Ingebrigtsen and Romner 1996, Missler et al. 1997b; Woertgen et al. 1997; Ingebrigtsen et al. 1999; Raabe et al. 1999a, 1999b; Elting et al. 2000). Both blood and CSF S100B levels have been shown to be reliable biomarkers to predict outcomes in various clinical conditions, when measured against functional scores, symptom inventories or measures of neuropsychological impairment, in both brain trauma and brain insults associated with cardiovascular disorders (Abraha et al. 1997; Rothoerl et al. 1998; Raabe et al. 1999a,b; Woertgen et al. 1999; Pleines et al. 2001; Hayakata et al. 2004; Savola et al. 2004; Vos et al. 2004, 2010; Foerch et al. 2005; Sanchez-Peña et al. 2008; Moritz et al. 2010). Serum S100B concentrations have even been proposed as a marker of brain death regardless of whether this is caused by trauma or vascular rupture (Regner et al. 2001). Data have also been reported indicating a direct involvement of S100B overproduction, as a sign of maladaptive astrocytic activation, in pathogenic mechanisms accompanying brain ischemia (Asano et al. 2005; Mori et al. 2008). Interestingly, the degree of systemic inflammation, as evaluated by C Reactive Protein measurements, has been shown to be associated with S100B concentration in subjects with acute ischemic stroke, independently of the size of the ischemic lesion (Beer et al. 2010). It should be mentioned, in this respect, that the role of S100B in injuries to the CNS has been likened to that of C-reactive protein as a biomarker of systemic inflammation (Sen and Belli 2007). Thus, the origin of S100B – which may be either leaked from damaged cells and/or secreted – is still an open question. The secretion of the protein and, in any case, its participation in pathogenic events, would offer new and interesting perspectives in both pathogenic and therapeutic terms. Some studies have indicated an extra-cerebral source for blood S100B both in trauma patients and in experimental models of trauma, where S100B was increased even in the absence of head injuries (Anderson et al. 2001a; Pelinka et al. 2003a,b). An extracerebral source of serum S100B was also found during cardiac surgery, leading to the proposal that fat, muscle or bone marrow may be the origin of the protein (Anderson et al. 2001b; Missler et al. 2002). These studies raised questions concerning the reliability of S100B as a marker of brain injury in trauma patients (Pham et al. 2010). However, an extracerebral source of S100B would not be surprising, bearing in mind the possibility that secreted S100B may actively participate in the injury process, as an inflammatory protein. In effect, adipocytes, which are known to be a site of concentration for S100B, are also regarded as a source of molecules involved in the inflammatory process, which might involve the brain (for reviews, Trayhurn and Wood 2004; Ouchi et al. 2011).

It should also be noted that serum levels of S100B have recently been shown to be related to the severity of major cardiac events (Li et al. 2011a). Enhanced serum levels have already been found in patients with either dilated cardiomyopathy or ischemic heart disease (Mazzini et al. 2007). In experimental conditions, S100B has been shown to be released from the ischemic heart (Mazzini et al. 2005; Cai et al. 2011), where it has also been shown to be induced and to promote left ventricular remodeling (Mazzini et al. 2005; Tsoporis et al. 2005). In addition, both S100B and its putative receptor RAGE have been shown to be up-regulated in the ischemic myocardium, hinting at an active/reactive role of the protein also in this pathological condition (Mazzini et al. 2005; Bucciarelli et al. 2006; Tsoporis et al. 2010).

S100B in tumors

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

S100B has been detected in CSF of patients with brain tumors (Michetti et al. 1980), and blood S100B has even been proposed as an early predictor of brain metastases (Vogelbaum et al. 2005; Marchi et al. 2008), its increase in serum being essentially attributed to the blood–brain barrier lesion accompanying the tumor (Kanner et al. 2003). However, the widest diagnostic use of S100B and the majority of studies to investigate blood S100B in tumors are directed not towards brain tumors but to melanoma, which also is of neuroectodermal origin.Following the earlier finding of S100B in human melanocytes and melanoma tissue (Cocchia et al. 1981) the protein has become a well established and widely used immunohistochemical marker for pigmented skin lesions (Springall et al. 1983; Cochran et al. 1993), and a positive immunostaining for S100B antigen in malignant melanomas has been found to correspond to the areas with an increased proliferation rate (Sviatoha et al. 2010). After initial studies supporting the clinical significance of serum S100B levels in melanoma (Guo et al. 1995; Henze et al. 1997), these levels in serum are currently the most widely used biomarker in malignant melanoma patients, with special regard to monitoring the progression of the disease and to evaluating the efficacy of therapy (Gogas et al. 2009; Bouwhuis et al. 2011). Bearing in mind that the release of S100B exerts an autocrine/paracrine effect, so that S100B may putatively be regarded as an inflammatory danger signal protein, the possibility that an abnormal presence in tumor microenvironments may underlie carcinogenesis and tumor progression is especially intriguing, and is even consistent with emerging views involving inflammatory processes in carcinogenesis (Coffelt and Scandurro 2008; Srikrishna and Freeze 2009). It might also be relevant in this respect that RAGE, which is regarded as an extracellular receptor for S100B and for DAMPs in general (Hofmann et al. 1999; Foell et al. 2007; Bianchi et al. 2011), is known to play a role in tumor development, progression and metastasis in several cancers, including melanoma (Abe et al. 2004; Logsdon et al. 2007; Sparvero et al. 2009). It is also interesting that intracellular S100B, which is usually over-expressed in melanoma, has been shown to interact with and down-regulate the tumor suppressor protein p53. Thus, S100B has been proposed as a candidate to contribute to tumorigenesis, and a program is under way to develop a drug that disrupts the S100B–p53 interaction as a means to restore functional p53 in melanoma cells (Lin et al. 2001, 2010; Markowitz et al. 2004; Wilder et al. 2010). Elevated serum levels of S100B have also been shown to predict reduced disease-free survival in breast cancer patients (McIlroy et al. 2010).

S100B in neuroinflammatory/neurodegenerative disorders

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

As noted above, the S100B protein was detected for the first time in extracellular biological fluids (CSF) of MS patients in concomitance with the acute phase of exacerbation, being essentially undetectable during remission (Michetti et al. 1979). At that time the appearance of the protein in biological fluids was regarded as a consequence of leakage from damaged cells. Today, the growing recognition that S100B may be regarded as a released neuroinflammatory protein makes it possible to reinterpret the original data as indicating the active participation of S100B in the exacerbation phase of MS. A subsequent longitudinal study that monitored the CSF of MS patients revealed a peak followed by a decrease (Massaro et al. 1985). When comparing MS subgroups, a significant trend of increasing CSF S100B levels from primary progressive to secondary progressive to relapsing-remitting MS was observed (Petzold et al. 2002). The observation of increased S100B concentrations in the exacerbation phase was also extended to the serum (Missler et al. 1997a). More recently, S100B levels in bodily fluids have also been cast as candidates for a useful tool to monitor immunosuppressive therapy in MS patients (Bartosik-Psujek et al. 2011). Recent studies have also shown the usefulness of both CSF and serum S100B as markers for neuromyelitis optica, which is regarded as a neurological inflammatory disease related to MS (Misu et al. 2009; Fujii et al. 2011).

Among the classic neurodegenerative disorders in which the possible involvement of S100B both as a biomarker and, more importantly, as a pathogenic effector has been intensively studied is Alzheimer’s disease (AD). There is evidence to support the thesis that S100B, released at high concentrations after prolonged activation of astrocytes, plays a detrimental role in the pathogenesis of AD. This includes the findings that S100B is up-regulated in AD tissues (Griffin et al. 1989; Marshak et al. 1992; Sheng et al. 1994, 1996; Van Eldik and Griffin 1994; Mrak et al. 1996), that the over-expression of S100B exacerbates cerebral amyloidosis in the Tg2576 mouse model of AD (Mori et al. 2010), that an AD-like pathology is attenuated in the aged Tg2576 model by pharmacological blockade (arundic acid) of S100B biosynthesis (Mori et al. 2006). Notwithstanding these observations, reports of S100B in the CSF or serum of AD patients appear to be conflicting. Surprisingly, serum S100B concentrations have been found to be lower in AD patients when compared with elderly controls, with no correlation with MRI-based assessment of brain atrophy (Chaves et al. 2010). However, correlations have been reported between CSF S100B levels and AD brain atrophy or cognitive status as measured by the Mini Mental State Exam score (Peskind et al. 2001; Petzold et al. 2003), while, on the other hand, a previous study did not find appreciable differences between CSF S100B concentrations in AD patients and controls (Nooijen et al. 1997). Thus, additional studies will be needed to define clearly the behavior of S100B, in the serum and CSF of AD patients. However, bearing in mind the bulk of information suggesting that over-expressed S100B may participate in the AD pathogenic process, and in order to explain why elevated levels of the protein have been found only in CSF and not in serum, the possibility might even be taken into account that the phenomena involving S100B are segregated to the brain compartment.

A restricted number of studies has been performed to date on S100B in ALS. The protein has been shown to be up-regulated in astrocytes and even in motor neurons in human spinal cord of ALS patients; the phenomenon was interpreted as a protective response (Migheli et al. 1999). Interestingly, in this respect, S100B levels in CSF have been shown to be inversely correlated with survival time in ALS patients (Süssmuth et al. 2010). However, the only study of S100B in the serum of ALS patients showed a decrease in the protein, the finding being regarded as a sign of reduced neurotrophic activity in these patients (Otto et al. 1998). Further studies of S100B in the bodily fluids of ALS patients will be needed in order to clarify these results, while the possibility that phenomena involving S100B are segregated to the brain compartment might be taken into account also in the case of ALS.

S100B transgenic mice have recently been reported to develop features of Parkinson’s disease (PD), leading to the hypothesis that S100B may be involved in the pathogenesis of this disease (Liu et al. 2011). However, no significant difference has been observed in serum S100B concentrations between PD patients and controls, although some correlation between S100B levels and scales indicating the clinical severity of the disease has been observed. It should be noted that the PD patients enrolled in this study continued treatment with dopaminergic agonists, which might have influenced the results (Schaf et al. 2005).

Finally, recent studies on human duodenal and rectal biopsies have demonstrated that the over-expression and release of S100B, which is a constituent of enteric glia, correlate with the inflammatory status of the gut in celiac disease and ulcerative colitis, playing an active role in the NO-dependent inflammation that underlies these diseases (Esposito et al. 2007; Cirillo et al. 2009). Studies correlating these findings with levels of S100B in bodily fluids or even in feces are currently lacking, although they appear to promise interesting developments both for early diagnosis and therapy.

S100B in psychiatric disorders

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

After earlier studies indicating an immune reaction to S100B in psychiatric patients (Jankovićet al. 1980, 1982), interest in S100B as a marker of brain injury led to the finding of elevated plasma levels of S100B in schizophrenic patients, which was regarded as an indication of structural brain damage (Wiesmann et al. 1999). While all patients examined were on neuroleptic medication, this finding was reproduced in unmedicated patients (Lara et al. 2001). However, conflicting results were obtained concerning the decrease or increase in serum S100B levels in relation to medication, possibly caused by the different therapies used. (Rothermundt et al. 2001b; Schroeter et al. 2003; Zhang et al. 2010). Interestingly, S100B blood levels have been shown to be correlated with negative symptomatology as measured using the Positive and Negative Syndrome Scale, and patients with persistent negative symptoms showed constantly high serum S100B concentrations, possibly associated with a poor response to therapy (Rothermundt et al. 2001b, 2004b). Parallel increases in S100B levels have also been found in CSF and blood of schizophrenic patients, supporting the possibility that serum measures reflect the S100B concentration in CSF and, likely, in the brain, where an astrocytic dysfunction has been hypothesized (Rothermundt et al. 2004a). Interestingly, a normalization of serum S100B levels in patients under antipsychotic treatment has been shown to be accompanied by a parallel increase in soluble RAGE, which is known to be a protective factor against a number of inflammatory diseases and which, in this case, might limit its ligand S100B (Steiner et al. 2009). The finding that increased S100B is not accompanied by alterations in other structural markers of neural cell types, such as glial fibrillary acidic protein, myelin basic protein and neuron specific enolase, has been regarded as an indication that S100B is actively released by astrocytes rather than leaked from damaged cells (Steiner et al. 2006). An additional indication of astrocyte activation as the source of released S100B was due to the observation that schizophrenic patients exhibiting high serum S100B levels also exhibited increased astrocytic metabolism as detected by MR-Spectroscopy (Rothermundt et al. 2007). However, recent studies have correlated serum S100B levels in schizophrenic patients with insulin resistance (Steiner et al. 2010b), proposing an association between S100B and disturbances of energy metabolism in schizophrenia, and suggesting that adipocytes may be a source of serum S100B in these patients too. Interestingly, S100B serum levels have also been shown to be related to body mass index in healthy subjects (Steiner et al. 2010a) and to decrease in anorexic patients, normalizing after weight gain (Holtkamp et al. 2008). The extension of studies of S100B in schizophrenia to include extraneural districts is not surprising, as this disease has already been related to disturbances leading to inflammatory and/or metabolic consequences (for reviews, Dantzer et al. 2008; Brown 2011). In particular, adipose tissue, which is a site of concentration for S100B, is also known to be a source of molecules involved in the inflammatory process (for reviews, Trayhurn and Wood 2004; Ouchi et al. 2011).

Increased levels of S100B have also been detected in both the CSF and serum of patients affected by major depressive disorder, as well as in the serum of patients with bipolar disorder, and have been regarded essentially as an index of astrocytic involvement (Graabe et al. 2001; Rothermundt et al. 2001a; Machado-Vieira et al. 2002; Andreazza et al. 2007). As for schizophrenic patients, conflicting results have been obtained after treatment, with both increases and decreases in serum S100B levels being reported (Schroeter et al. 2002; Arolt et al. 2003) and attributed respectively to an increase in neuroprotective activity of the protein and to an index of reduced astrocytic alteration. It is also noteworthy that serum S100B levels have even been shown to be significantly higher and correlated with suicidal intention in adolescent patients, regardless of the psychiatric diagnosis. The protein was proposed as a biomarker of the severity of the risk of suicide in these patients; the high concentration of S100B in the blood of these patients was attributed to a blood-brain barrier disruption caused by an inflammatory process (Falcone et al. 2010).

Further investigation into the possible role of S100B as a biomarker and putative effector in psychiatric disorders is an intriguing challenge for research on this protein, as well as on these diseases, and could lead to more a complete understanding of these disorders and of neuroinflammatory/neurodegenerative diseases in general. It might also help to throw light on a series of interesting but conflicting studies aimed at investigating possible connections between variations of the S100B gene and psychiatric diseases, and even personality traits (Liu et al. 2005; Roche et al. 2007; Yang et al. 2008, 2009; Suchankova et al. 2011; Zhai et al. 2011).

S100B in physiological conditions of stress

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

Several studies have shown increases in serum S100B during vigorous physical activity, including agonistic sports such as swimming, running, boxing, soccer and basketball (Otto et al. 2000; Dietrich et al. 2003; Hasselblatt et al. 2004; Schulpis et al. 2007). The phenomenon has been essentially attributed to brain distress accompanying physical activity or to lipolysis following strong muscle contraction. Increased S100B has also been observed after vigorous physical activity in the saliva of professional sportsmen and healthy controls (non-professional sportsmen). Interestingly, a significant, increase in basic saliva S100B levels at rest has been observed in professional sportsmen compared with controls (Michetti et al. 2011). Thus, levels of S100B that are chronically higher than physiological levels might indicate some form of chronic inflammatory condition in professional sportsmen, although the possibility that S100B merely originates from skeletal myofibers, which have been reported to contain the protein (Arcuri et al. 2002), cannot be ruled out. It may be relevant in this respect that epidemiological studies have suggested, albeit not unequivocally, a relation between vigorous physical activity and neurodegenerative disorders such as ALS (Abel 2007; Armon 2007; Chio et al. 2009). In any case, as vigorous physical activity cannot reasonably be regarded as an acute pathological condition, the increase in S100B can hardly be considered a consequence of a leakage of the protein from damaged cells: a release related to the activity of the subjects should more reasonably be taken into consideration, suggesting a regulatory mechanism for the protein. In addition, S100B levels have recently been shown to be consistently increased in the blood and urine of physicians on duty, a condition that certainly cannot be regarded as pathological but which is characterized by mental, and possibly physical, activity as well as stress (Gazzolo et al. 2010). Notably, serum S100B concentrations in both mother and newborn have been shown to increase significantly after prolonged labor with vaginal delivery, which also constitutes a condition of stress (Schulpis et al. 2006). In addition, in experimental stress conditions an increase in S100B concentrations has also been observed in rats (Scaccianoce et al. 2004). Taken together, these data contribute to delineate a scenario in which the release of S100B may be regulated during physiological activities, possibly even participating, at high concentrations, in stress mechanisms.

Concluding remarks and future perspectives

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

The accumulated evidence outlined here confirms the established notion that the levels of S100B in biological fluids have an important role in risk stratification, targeting of therapies and prognosis in a series of pathological conditions from perinatal medicine to diseases of the elderly involving primarily, but not exclusively, the nervous system (Table 1). In addition, evidence is accumulating that the increased levels of this protein do not merely reflect its leakage from damaged (neural or non-neural) cell types. Synthesis and release of S100B appear to be physiologically regulated and, at high concentrations, to participate in inflammatory processes, highligthing the notion that S100B effectively can behave as a DAMP molecule or as a cytokine. The consideration that S100B is physiologically regulated raises at least two questions: (i) which mechanisms regulate S100B synthesis and release? (ii) which are the target cells of S100B activity? The first question offers a very promising field for future research and is closely associated with the origin of S100B found in biological fluids. The nervous system has to be regarded as the natural source of extracellular S100B, given that it is the main site of concentration and that the majority of pathological conditions associated with elevated levels of S100B in biological fluids that have been investigated to date involve this system. Another site of concentration for S100B is adipose tissue, which is regarded as a source of paracrine and circulating molecules with active roles in regulation (for reviews, Kershaw and Flier 2004; Halberg et al. 2008). It is also interesting to note that in experimental conditions S100B has been shown to be released by adipose tissue under hormonal control (Suzuki et al. 1984; Suzuki and Kato 1985). This tissue has to be regarded as a potential source of S100B in biological fluids for at least some of the conditions mentioned here.

Table 1.   Variations of S100B levels in human bodily fluids in different physiological/pathological conditions
Bodily fluidConditionVariationReferences
CSFPerinatal hypoxia and post-hemorrhagic ventricular dilatation[UPWARDS ARROW]Blennow et al. 2001; Whitelaw et al. 2001
Acute brain injury[UPWARDS ARROW]Aurell et al. 1991; Persson et al. 1987
Brain tumors[UPWARDS ARROW]Michetti et al. 1980
Multiple sclerosis[UPWARDS ARROW]Michetti et al. 1979; Massaro et al. 1985
Neuromyelitis optica[UPWARDS ARROW]Misu et al. 2009
Alzheimer diseaseNooijen et al. 1997
 [UPWARDS ARROW]Peskind et al. 2001; Petzold et al. 2003
Amyotrophic lateral sclerosis[UPWARDS ARROW]Süssmuth et al. 2010
Schizophrenia[UPWARDS ARROW]Rothermundt et al. 2004a
Depressive/bipolar disorders[UPWARDS ARROW]Graabe et al. 2001
BloodIntrauterine growth retard (umbilical blood)[UPWARDS ARROW]Gazzolo et al. 2002b
Neonatal intraventricular haemorrhage (maternal blood)[UPWARDS ARROW]Gazzolo et al. 2006
Acute brain injury[UPWARDS ARROW]Abraha et al. 1997; Anderson et al. 2001a; Beer et al. 2010; Elting et al. 2000; Foerch et al. 2005; Ingebrigtsen and Romner 1996; Pelinka et al. 2003b; Pleines et al. 2001; Raabe et al. 1999a,b; Regner et al. 2001; Rothoerl et al. 1998; Savola et al. 2004; Vos et al. 2010; Woertgen et al. 1997
Major cardiac events[UPWARDS ARROW]Anderson et al. 2001b; Li et al. 2011a; Mazzini et al. 2007; Missler et al. 2002
Brain metastases[UPWARDS ARROW]Marchi et al. 2008; Vogelbaum et al. 2005
Melanoma[UPWARDS ARROW]Bouwhuis et al. 2011 Guo et al. 1995; Henze et al. 1997
Breast cancer[UPWARDS ARROW]McIlroy et al. 2010
Multiple sclerosis[UPWARDS ARROW]Missler et al. 1997a
Neuromyelitis optica[UPWARDS ARROW]Fujii et al. 2011
Alzheimer disease[DOWNWARDS ARROW]Chaves et al. 2010
Amyotrophic lateral sclerosis[DOWNWARDS ARROW]Otto et al. 1998
Parkinson diseaseSchaf et al. 2005
Schizophrenia[UPWARDS ARROW]Lara et al. 2001; Rothermundt et al. 2001b, 2004b; Steiner et al. 2010b; Wiesmann et al. 1999
Depressive/bipolar disorders[UPWARDS ARROW]Machado-Vieira et al. 2002; Andreazza et al. 2007
Obesity[UPWARDS ARROW]Steiner et al. 2010a
Vigorous physical activity[UPWARDS ARROW]Otto et al.2000; Dietrich et al. 2003; Hasselblatt et al. 2004; Schulpis et al. 2007
Stressfull activity[UPWARDS ARROW]Gazzolo et al. 2010
Prolonged labor (maternal and umbilical blood)[UPWARDS ARROW]Schulpis et al. 2006
UrineAsphyxiated fullterm infants[UPWARDS ARROW]Gazzolo et al. 2003d
Preterm newborns with Intraventricular haemorrage[UPWARDS ARROW]Gazzolo et al. 2001b
Neonatal hypoxic-ischemic encephalopathy[UPWARDS ARROW]Liu et al. 2010
Early neonatal death[UPWARDS ARROW]Gazzolo et al. 2005a, 2009
Stressfull activity[UPWARDS ARROW]Gazzolo et al. 2010
SalivaVigorous physical activity[UPWARDS ARROW]Michetti et al. 2011
Amniotic fluidIntratrauterine death[UPWARDS ARROW]Florio et al. 2004
CNS malformations[UPWARDS ARROW]Sindic et al. 1984
Trisomy 21[UPWARDS ARROW]Gazzolo et al. 2003a; Tort et al.2004
Monoamniotic twin pregnancy[UPWARDS ARROW]Gazzolo et al. 2003c
MilkMilk maturation[UPWARDS ARROW]Gazzolo et al. 2003e

Neurons are regarded as natural target cells for S100B, while a stimulating effect on microglia (Petrova et al. 2000; Adami et al. 2001; Bianchi et al. 2011) and an autocrine regulatory effect on astrocytes (Petrova et al. 2000; Ponath et al. 2007) have also been reported, and likely mediate the S100B-dependent effects. It is reasonable to hypothesize that circulating S100B also produces effects on extra-neural cell types, the identification of which is also a promising field of research. In any case, the scenario in which the level of S100B is not merely a consequence of cell damage, but (also) an index of a process in which the protein may be an important effector, opens the prospect of regarding this protein not only as a biomarker but also as a potential therapeutic target for treatment of the pathological conditions in which it is involved.

Finally, bearing in mind the possibility that the involvement of S100B in pathological conditions may extend outside the nervous system, an as yet unknown systemic activity for this protein might be envisaged, pointing the way for research to identify a unifying biological role for this still challenging protein.

Acknowledgements

  1. Top of page
  2. Abstract
  3. S100B in perinatal medicine
  4. S100B in acute brain injury, and more
  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References

This work was partially supported by a grant from the Università Cattolica del S. Cuore to FM. We are grateful to Ms Carla Annibaldi and Mr Roberto Passalacqua for their help in the editing of this manuscript.

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  5. S100B in tumors
  6. S100B in neuroinflammatory/neurodegenerative disorders
  7. S100B in psychiatric disorders
  8. S100B in physiological conditions of stress
  9. Concluding remarks and future perspectives
  10. Acknowledgements
  11. References
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