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Which diseases respond best to blocking of a specific biologic pathway is not always apparent. In the case of reducing interleukin-1 (IL-1) activities, there is still much that is open for exploration. Although the IL-1 Trap (1), antibodies to IL-1β, antibodies to the IL-1 receptor type I (IL-1RI), and oral inhibitors of caspase 1 are undergoing clinical trials, anakinra, the recombinant form of the naturally occurring IL-1R antagonist (IL-1Ra), is the only agent presently approved for reducing IL-1 activities. Anakinra is approved in the US and Europe for treating the signs, symptoms, and structural damage in patients with moderate-to-severe rheumatoid arthritis. More than 100,000 patients have been treated with anakinra, some for as long as 5 years, and many continue to have benefit. But compared with agents that neutralize tumor necrosis factor (TNF), clinical responses to anakinra may require several weeks or even months of daily treatment before they are apparent. Anakinra binds to the IL-1RI as a pure receptor antagonist, preventing bona fide IL-1 from binding to and activating a cell. Therefore, following subcutaneous injection of anakinra, blocking of IL-1 receptors in the inflamed synovial space is the therapeutic objective in rheumatoid arthritis, and with a receptor antagonist, sustaining sufficient receptor blockade is concentration and time dependent. In contrast, direct intraarticular injection of anakinra into osteoarthritic joints provides some patients with pain relief lasting several weeks (ref. 2 and Weiss J: personal communication). Compared with TNF blockers in patients with rheumatoid arthritis, anakinra has a remarkable safety record.

There are, however, several systemic multisystem syndromes which respond to anakinra within hours or days, revealing a fundamental role for IL-1 in inflammation. These syndromes are characterized by recurrent fevers, neutrophilic leukocytosis, thrombocytosis, elevated levels of serum amyloid A and C-reactive protein, associated with rashes, and diffuse and/or frank deforming arthritis as well as hearing loss, developmental delay, and low grade aseptic meningitis in children. The symptoms are triggered by mild stresses, such as exposure to cold or routine viral infections of the upper respiratory tract. Anakinra rapidly and dramatically arrests each of the multisystem manifestations of these syndromes, commonly within hours or a few days. Upon cessation of anakinra therapy, clinical signs and symptoms, as well as biochemical and hematologic abnormalities, rebound within days.

These syndromes often occur in patients with single point mutations in a gene called cold-induced autoinflammatory syndrome 1 (CIAS1) (now termed NALP3) where the particular protein affected by the mutation is located. The mutations result in single amino acid changes in one of the proteins controlling the activity of the intracellular proteolytic enzyme called caspase 1 (formerly the IL-1β–converting enzyme). This enzyme converts the inactive IL-1β precursor molecule into active IL-1β. Active IL-1β is then released from the cell by a tightly controlled secretory process (3). Indeed, monocytes from patients with a mutation release greater amounts of IL-1β than monocytes from subjects without a mutation (4). However, there are patients with near identical syndromes who lack this particular mutation but experience the same dramatic resolution of disease activity within 24 hours of the first injection of anakinra (5–7).

The mutation is also absent in patients with refractory adult-onset Still's disease, where a rapid resolution of the disease activity is observed within hours or days of treatment with anakinra (8–11). Anakinra is now the treatment of choice in patients with steroid-refractory adult-onset Still's disease, mutations in NALP3, and Schnitzler's syndrome (van der Meer J: personal communication). Systemic juvenile rheumatoid arthritis is likely to be another disease best treated with anakinra (12). Familial Mediterranean fever, a classic disease involving recurrent attacks of acute serosal inflammation, is also the result of a genetic defect in IL-1β regulation (13). In patients in whom the disease does not respond to colchicine, anakinra rapidly arrests the attacks. The most unexpected response to anakinra has been reported in an inherited disease due to a mutation in the regulation of TNF, not a mutation in IL-1 regulation. These patients experience recurrent fevers and systemic inflammation due to overactivity of TNF, but show a response to anakinra (14).

The paradox of IL-1Ra in treating local and systemic disease

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

Fever, neutrophilia, and high levels of acute-phase proteins often characterize systemic inflammation, and skin rashes are indicative of endothelial cell activation. This is certainly the case in patients with NALP3 gene mutations and also in patients with adult-onset Still's disease. Peak plasma levels of anakinra are between 1 and 1.5 μg/ml 3–4 hours after a subcutaneous injection, and upon entering the intravascular space, endothelial receptors for IL-1 have become saturated. However, the effect is short-lived, and plasma levels of anakinra return to baseline levels by 24 hours. Occupancy of the endothelial IL-1 receptors by anakinra is a global effect, resulting in blocking of all IL-1–mediated systemic inflammation. This action could explain the paradox of responses to anakinra; in systemic disease, endothelial IL-1 receptors are blocked rapidly and inflammation is arrested, whereas in joint disease, saturation of IL-1 receptors is dependent on synovial penetration, with clinical improvement and slowing of structural damage being observed only after prolonged use. Achieving pharmacologic occupancy of any receptor by a specific antagonist is no easy task, particularly when the receptor is not restricted to a particular tissue. In humans with rheumatoid arthritis, blocking of the type I receptor with anakinra is further complicated by its rapid renal clearance.

Clearly, the most marked responses to anakinra have been observed in patients with adult-onset Still's disease (9, 10), macrophage activation syndrome, familial Mediterranean fever, or mutations in the NALP3 gene. These mutations can cause Muckle-Wells syndrome (15), neonatal-onset multisystem inflammatory disease (7), and familial cold autoinflammatory syndrome (16). Although it is often difficult to demonstrate elevated circulating levels of IL-1β in these patients, the rapid reduction in fever, neutrophilia, and acute-phase reactants by anakinra demonstrates that these are IL-1–mediated diseases, since IL-1Ra blocks only the IL-1 receptor. IL-1 is the most pyrogenic of the fever-inducing cytokines (17); morever, IL-1 is a bone marrow stimulant, particularly of neutrophilic responses (18). In contrast, TNFα suppresses bone marrow functions. IL-1 induction of endothelial IL-6 likely accounts for the rise in hepatic acute-phase proteins and thrombocytosis (16). As shown in Figure 1, the endothelium is a primary target for the efficacy of anakinra in these systemic inflammatory diseases.

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Figure 1. A model for interleukin-1 (IL-1) in systemic inflammation. Cells comprising the endothelial or serosal surface express the IL-1 receptor type I. Under conditions of stimulation, monocytes or macrophages adhere to these surfaces and synthesize the inactive IL-1β precursor. This is cleaved by caspase 1, releasing the active cytokine. Active IL-1β enters the circulation, where it affects the bone marrow by releasing neutrophils and the hypothalamus by inducing fever. IL-1β can also activate inflammatory processes in the adjacent endothelial cell, including the production of adhesion molecules, chemokines, and IL-6. Circulating IL-6 increases and, reaching the liver, induces acute-phase protein synthesis. Also shown is a cell expressing membrane IL-1α. Similar to secreted IL-1β, membrane-bound IL-1α (see Figure 3) activates the IL-1 type I receptors on the endothelium. Either natural IL-1 receptor antagonist (IL-1Ra) or recombinant anakinra blocks endothelial IL-1 receptors and arrests each of the events.

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The lesson learned from treating these rare diseases with specific blockade of IL-1 is that the clinical, hematologic, and biochemical manifestations are hardly rare; in fact, they are the hallmarks of systemic inflammation. These clinical findings also place IL-1 in a unique position in the cascade of cytokines during inflammation. They raise the question as to whether there are “unique IL-1 diseases” or whether IL-1 mediates the inflammation induced by more distal cytokines, such as TNF or IL-18. It should be noted that many patients with or without the NALP3 mutation, as well as patients with adult-onset Still's disease, were initially treated with infliximab or etanercept with partial responses, suggesting that neutralization of TNF results in decreased IL-1 activity in those patients. This author supports the concept that IL-1 contributes to the inflammatory component of most diseases and that efficacy of antibodies to TNF is due, in part, to a reduction in IL-1 activities. However, uniquely IL-1–mediated diseases do exist due to dysfunction in IL-1 gene expression, processing, and release, as well as receptor expression.

How best to reduce IL-1 activities: receptor antagonism and decoy receptors

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

It would seem that there is no need to have any other agent but anakinra to treat IL-1–mediated inflammation. However, there are several mechanisms by which nature limits IL-1 activity and each can be exploited for novel therapeutic targets. For treatment of any disease, blocking of the most proximal defect in the pathologic process reduces collateral damage. In the case of anticytokine therapies, reducing collateral damage means sparing impairment of host defenses. In rheumatoid arthritis, sparing host defenses becomes a particularly important consideration for long-term therapy since the disease itself exhibits a markedly reduced T cell repertoire even in young patients (19). T cell function is also reduced by the concurrent use of disease-modifying antirheumatic drugs, and the aging process itself is a progressive state of T lymphocyte senescence.

In a report in this issue of Arthritis & Rheumatism, Smeets et al (20) show that there is a selective effect on lymphocyte activation when 2 different methods for blocking IL-1 are compared in the mouse model of collagen-induced arthritis (CIA). They compared overexpression of IL-1Ra with overexpression of the soluble form of the IL-1 coreceptor, termed the IL-1 receptor accessory protein (sIL-1RAcP). The results were unexpected. Although overexpression of either IL-1Ra or sIL-1RAcP ameliorated joint and systemic manifestations of CIA in mice, lymphocyte populations affected by IL-1 blockade were not similar. The differential effects of the 2 IL-1 blockers occurred between B and T lymphocytes. With the report that antibodies to CD20 on B cells reduce disease severity in patients with rheumatoid arthritis, targeting B lymphocyte function in models of rheumatoid arthritis takes on increasing importance.

In the CIA model, both IL-1 blockers suppressed the levels of anticollagen IgG2a, as well as the production of IL-6. But, whereas overexpression of IL-1Ra blocked NF-κB signaling in both T and B lymphocytes, overexpression of sIL-1RAcP reduced activation only in B lymphocytes, sparing T cell activation. The findings have implications regarding the long-term safety of treating rheumatoid arthritis with anticytokine therapies. Sparing T lymphocyte function is the lesson from the human immunodeficiency virus 1 epidemic. When comparing TNF blocking therapies to anakinra treatment, there is a remarkable difference in the number of opportunistic infections between reducing TNFα and IL-1 activities (21). In marked contrast, there are hardly any voluntary reports, or findings in controlled trials, of opportunistic infections in rheumatoid arthritis patients treated with anakinra (22), including populations at high risk for reactivation of Mycobacterium tuberculosis infections (23). These clinical realities support the concept that preservation of T lymphocyte function using anticytokine therapies is a worthy objective for long-term safety. For that reason, the results of the study by Smeets et al need closer examination.

What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

The findings of Smeets and coworkers are novel with regard to the pathogenesis and treatment of rheumatoid arthritis, but not entirely surprising regarding the biology of IL-1 and its receptors. The difference between IL-1Ra and sIL1-RAcP in reducing IL-1 is best understood in terms of preventing IL-1 activity at the level of the cell surface compared with the extracellular space. IL-1Ra blocks IL-1 surface receptors, which are present on all nucleated cells, primarily by occupancy of the ligand-binding IL-1RI; in fact, IL-1Ra binds to this receptor with a greater affinity than IL-1β. Occupancy of IL-1RI by IL-1Ra prevents the recruitment of the IL-1RAcP coreceptor to form the heterodimer that initiates signal transduction (Figure 2A). However, there is another cell surface receptor for IL-1, termed IL-1RII. This receptor, which lacks a cytoplasmic domain and cannot participate in signal transduction, functions as a decoy receptor by competitive binding to IL-1β (24) (Figure 2B). The type II receptor can also form an inactive complex with the IL-1RAcP (Figure 2B), preventing the cell from participating in signal transduction (25, 26).

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Figure 2. Natural mechanisms for reducing interleukin-1 (IL-1) activities. A, Most cells express both components of the IL-1 receptor complex. These receptors comprise 3 immunoglobulin-like domains and an intracellular domain containing the Toll-like regions (stippled area). IL-1 receptor type I (IL-1RI) binds IL-1β, which then recruits the IL-1 receptor accessory protein (IL-1RAcP). This forms the high-affinity heterodimeric signaling complex. X-ray diffraction studies of co-crystals of the complex revealed that IL-1β binds to the third domain of IL-1RI and that the first domain undergoes a structural change in shape. Proximity to the intracellular Toll–IL-1 receptor (TIR) domains of each receptor chain (2-headed arrow) initiates a signal. When the receptor antagonist (IL-1Ra) occupies the IL-1RI, the IL-1RAcP is not recruited, and there is no heterodimer and no signal. The affinity of IL-1Ra for the IL-1RI is greater than that for IL-1β. Endogenous IL-1Ra functions to limit the activities of IL-1 since mice deficient in IL-1Ra spontaneously develop inflammatory diseases including arteritis (39) and a destructive rheumatoid arthritis–like joint disease (40). There is no evidence that either IL-1β or IL-1Ra can bind to the IL-1RAcP alone, and hence this receptor chain is classified as an essential coreceptor. B, In neutrophils, monocyte/macrophages, B lymphocytes, and chondrocytes, another IL-1 receptor chain is expressed, termed the IL-1 receptor type II (IL-1RII). This receptor chain is also called the “decoy” receptor since it has a greater binding affinity to IL-1β than the type I receptor and hence serves as a “sink” for the ligand. This receptor lacks a significant intracellular segment, and there is no TIR domain. The IL-1RII binds IL-1β but does not signal (24). IL-1β bound to the IL-1RII can also form a high-affinity complex with the IL-1RAcP (25, 26). Cells also expressing this receptor benefit from blockade of the type I receptor by IL-1Ra as well as the decoy effect of the type II receptor. C, The extracellular (also termed soluble) domains of each of the IL-1 receptor chains exist in the plasma as well as in interstitial fluids. In general, their concentrations in body fluids increase 2–4-fold in disease states. The soluble IL-1RI (sIL-1RI) binds IL-1Ra with a greater affinity than that for IL-1α or IL-1β. The soluble type I receptor may act as a sink for IL-1Ra at natural as well as pharmacologic levels. Not surprisingly, administration of sIL-1RI was not effective in reducing IL-1 activities in patients with rheumatoid arthritis (41) or in human volunteers injected with endotoxin (42). The sIL-1RII binds IL-1β and neutralizes its activities. The sIL-1RAcP does not bind IL-1β but rather forms a high-affinity complex with the sIL-1RII and neutralizes IL-1β activities (27). D, This cell is exposed to high levels of the soluble form of the IL-1RAcP. Although the source of sIL-1RAcP can be proteolytic release of the cell-bound IL-1RAcP, constitutive secretion of sIL-1RAcP from hepatocytes of an mRNA splice variant (29) likely contributes to high levels in body fluids. Soluble IL-1RAcP may form a complex with either IL-1RI or IL-1RII and IL-1β in vivo but without initiating a signal (29). Another splice variant of constitutively secreted sIL-1RAcP exists (30). During cell activation, there appears to be a down-regulation of the membrane form of IL-1RAcP and an increase in the translation of the constitutively secreted sIL-1RAcP (30). In cells primarily expressing the type II IL-1 receptor, the formation of the inactive complex of sIL-1RAcP with the cell-bound type II receptor provides for enhanced inhibition of IL-1 activities. In vivo, the combination of the sIL-1RII and sIL-1RAcP results in a greater inhibition of IL-1 activity than does sIL-1RII alone (27).

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Shedding of IL-1 cell surface receptors by proteolytic cleavage results in circulating levels of only the extracellular domains, termed soluble receptors. As shown in Figure 2C, sIL-1RI can bind IL-1Ra, IL-1α, or IL-1β. However, the soluble type I receptor has a higher affinity for IL-1Ra than for IL-1β, and is more likely to bind the antagonist than IL-1α or IL-1β. There is no evidence that sIL-1RAcP alone can neutralize IL-1 activities. There is also a paucity of in vitro data that the natural soluble type I receptor reacts with the soluble IL-1RAcP to form a complex with either IL-1α or IL-1β, but these complexes may form in vivo and may explain the data obtained by Smeets et al. Alternatively, it is possible to construct a high-affinity “trap” for IL-1β by combining the extracellular domains of both the IL-1RI and IL-1RAcP as a neutralization strategy. In fact, a recombinant bivalent chimeric containing the extracellular domains of both IL-1RI and IL-1RAcP linked to Fc, termed the IL-1 Trap, has been engineered (1). Of clinical significance, the IL-1 Trap preferentially binds IL-1β and has been effective in clinical trials for the treatment of rheumatoid arthritis. The IL-1 Trap is also being studied in other inflammatory diseases.

Unlike the soluble type I receptor, the soluble type II receptor preferentially binds IL-1β and not IL-1Ra (Figure 2C). Furthermore, once IL-1β binds to the soluble type II receptor, sIL-1RAcP is recruited to form a complex with an affinity for IL-1β 100 times greater than that of sIL-1RII alone (27). This latter complex (Figure 2C) may be the dominant mechanism for the natural neutralization of IL-1β by endogenous soluble receptors. In monkeys, neutralization of IL-1β by sIL-1RII is greatly enhanced by sIL-1RAcP (27).

Several studies have demonstrated low (picogram and subpicogram/milliliter) levels of circulating IL-1β in human disease; however, levels of soluble type II receptor circulate in the nanogram/milliliter range (4–6 ng/ml). We now know that sIL-1RAcP circulates at an even greater concentration (median level 300 ng/ml) in healthy humans (27). Although most soluble receptors are generated by proteolytic cleavage from the cell surface receptors, this is apparently not the mechanism for high levels of sIL-1RAcP (27). It is likely that constitutive secretion of sIL-1RAcP explains the existence of these high levels. Supporting this concept is the existence of a splice variant of the IL-1RAcP, which lacks a transmembrane anchor (28–30). This sIL-1RAcP is synthesized and released by the liver in somewhat the same way IL-1Ra is released by the liver; as an acute-phase protein (31). In the report by Smeets and colleagues, overexpression of sIL-1RAcP likely formed a complex of IL-1β with sIL-1RII in the extracellular space (Figure 2C), with the cell surface IL-1RII (Figure 2D), or possibly with IL-1RI (Figure 2D). Thus, a large molar excess of sIL-1RAcP provides at least 3 mechanisms to entrap secreted IL-1β and reduce not only the arthritis, but also IL-6 production and antibodies to the collagen. In contrast, the sole mechanism for IL-1Ra is binding to the type I IL-1 surface receptor.

Cell selectivity of decoy IL-1R

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

The study by Smeets and coworkers revealed that sIL-1RAcP selectively reduces IL-1 activity on cells that express surface type II decoy receptors (B lymphocytes and chondrocytes). For example, B lymphocytes express 20-fold more type II receptors than type I receptors, but in T lymphocytes, this increase is only 5-fold. Relevant to IL-1–mediated cartilage breakdown and inhibition of proteoglycan synthesis, chondrocytes express an excess of type II receptors. As shown in Figure 2D, overexpression of sIL-1RAcP likely formed complexes on the cell surface of IL-1β bound to type II receptors. This complex as the type II receptor decoy mechanism was first proposed by Malinowsky et al (25) and Lang et al (26), and accounts for the ability of sIL-1RAcP to reduce B lymphocyte activation. It is thus likely that low levels of type II receptors on T lymphocytes prevent suppression of T lymphocytes in vivo and in vitro by sIL-1RAcP. Since IL-1Ra preferentially binds to the type I receptor, and since the type I receptor is present on all nucleated cells, IL-1Ra inhibited both B and T lymphocyte responses.

IL-1 effects on T and B lymphocyte functions

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

Several studies have established the adjuvant properties of IL-1, particularly IL-1β. The adjuvant activity is likely due to the induction of B lymphocyte growth factors such as IL-6. In studies using mice deficient in both IL-1α and IL-1β, the primary B cell functions of antibody production to T cell–independent antigens were normal (32). In addition, antibodies to other antigens such as lipopolysaccharide, and proliferative responses to mitogens, were unaffected in these mice. However, both primary and secondary antibody production against the T lymphocyte–dependent sheep red blood cell antigen was significantly reduced in mice deficient in both IL-1α and IL-1β (32). Furthermore, antibodies to sheep red blood cells are normal in IL-1α–deficient mice, suggesting a specific role for IL-1β, since antibodies to common antigens require T helper lymphocyte interactions with antigen-presenting cells. On the other hand, the presence of IL-1α, but not IL-1β, was required during skin sensitization to a chemical antigen (33). In this case, transfer of antigen-conjugated IL-1α–deficient epidermal cells is unable to prime T lymphocytes for sensitization. This result is not unexpected, since IL-1α but not IL-1β is constitutively expressed in epidermal cells.

Why 2 IL-1s?

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

Interpretation of the results of the study by Smeets and coworkers focuses on the interaction of sIL-1RAcP with IL-1RII, the decoy receptor binding primarily IL-1β. But there are 2 IL-1s, and there is no dearth of data that IL-1α has its place in causing IL-1–mediated disease. IL-1β is the secreted form of IL-1 (Figure 1) and, although circulating levels of IL-1β are measurable, these levels are usually in the low picogram/milliliter range, even in severe diseases such as sepsis. In contrast, the IL-1 precursor is not cleaved by caspase 1, IL-1α is not secreted from cells, and only in severe disease can one detect serum IL-1α, which may result from its release from dying cells. IL-1α remains intracellular, where it can function as a DNA binding transcription factor, and perhaps as an oncogene (34–36). As shown in Figure 3, the IL-1α precursor is biologically active when inserted into the cell's membrane, oriented in such a manner that it binds to the type I IL-1 receptor and initiates signal transduction (37). For example, activated macrophages expressing membrane IL-1α induce the chemokine IL-8 from endothelial cells, which is prevented by the presence of IL-1Ra (38); this mechanism of activation is commonly called “juxacrine” (Figure 3).

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Figure 3. Biologic activity of membrane-bound IL-1α. Myristolation sites in IL-1α allow the precursor form of the cytokine to be inserted into the cell's membrane, where it is biologically active. As shown on the left, membrane IL-1α is oriented such that it can bind to the IL-1RI surface receptor and recruit the IL-1RAcP. As with secreted IL-1β, the Toll domains (stippled areas) of both receptor chains trigger signal transduction. On the right, IL-1Ra occupancy of the type I receptor prevents the binding of membrane IL-1α, and no signal is transduced. See Figure 2 for definitions.

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Juxacrine stimulation occurs when a cytokine expressed on the surface of one cell triggers the specific cytokine receptor on an adjacent cell (cell–cell contact), since the two cells are in juxtaposition to each other. Membrane IL-1α employs this mechanism of activity. IL-1α that is processed and released from the cell has a higher affinity for the type I receptor than does IL-1β. Membrane IL-1α also triggers the type I receptor. Therefore, the response to anakinra in systemic inflammation likely includes blocking of the juxacrine activity of IL-1α (Figure 3) as well as blocking of IL-1β secreted from the cell.

Exploiting nature's mechanisms for limiting IL-1 activities

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

Are there better ways to achieve a reduction in IL-1 activities, particularly in localized disease? It is a general concept that IL-1–associated disease severity is regulated at the level of ligand production and activity, not the receptor level. For example, the IL-1 type I receptors are expressed on all cells in healthy subjects and increases of 2–3-fold occur in models of disease. On the other hand, in circulating monocytes and bone marrow macrophages, gene expression for IL-1β is absent under normal conditions but increases at least 100-fold with stimulation. Moreover, most of the messenger RNA coding for IL-1β is not translated into the IL-1β precursor, but instead degrades rapidly. The conversion of the precursor by caspase 1 to an active cytokine is tightly controlled. In fact, most of the IL-1β precursor that is synthesized is never cleaved despite the presence of constitutive caspase 1 in the same cell.

An elaborate complex of proteins termed the “IL-1β inflammasome” limits caspase 1 activity. The great lesson learned from the study of patients with a single point mutation in the NALP3 gene is that the “IL-1β inflammasome” has lost this tight control and that relatively minor stresses result in dramatic systemic and local disease. Thus, neutralization of IL-1β through sIL-1RAcP, IL-1 Trap, or inhibition of caspase 1 offers possible treatment options in these patients. However, there are patients without a mutation in this gene who also experience similar systemic IL-1–mediated disease, leaving the potential for novel therapies to reduce IL-1 activities. The implications of the study by Smeets and coworkers are that at pharmacologic levels, sIL-1RAcP may be an effective treatment option and may spare T lymphocyte activation by IL-1. Although the level of sIL-1RAcP that provides effective reduction in IL-1 activities is presently unknown, sIL-1RAcP has the advantage of functioning as a neutralizing mechanism (Figure 2C) as well as participating in the formation of decoy complexes on the cell surface (Figure 2D). The IL-1 Trap (1) already takes advantage of the high-affinity complex of IL-1β (or IL-1α) with the type I receptor and the sIL-1RAcP for neutralization of IL-1. Future studies will further elucidate these interactions and define more clearly the role of IL-1 in inflammatory diseases and clarify optimal strategies for treatment.

Acknowledgements

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES

The author thanks Drs. Avril Fitzgerald, Jos van der Meer, Richard Chou, Jonathan Kay, Daniel Kastner, Rafaela Goldbach-Mansky, Hal Hoffman, Peter Hawkins, Joerg Tschopp, Mihai Netea, and Judy Weiss for their contributions on the topic. The author thanks Professor Michael Martin for his critical evaluation of the manuscript.

REFERENCES

  1. Top of page
  2. The paradox of IL-1Ra in treating local and systemic disease
  3. How best to reduce IL-1 activities: receptor antagonism and decoy receptors
  4. What accounts for the differences between overexpression of IL-1Ra and sIL-1RAcP?
  5. Cell selectivity of decoy IL-1R
  6. IL-1 effects on T and B lymphocyte functions
  7. Why 2 IL-1s?
  8. Exploiting nature's mechanisms for limiting IL-1 activities
  9. Acknowledgements
  10. REFERENCES
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