A critical role for interleukin-1β in the progression of autoimmune diseases

International Immunopharmacology 17 (2013) 658–669

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International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp

Review

A critical role for interleukin-1β in the progression of autoimmune diseases Ruijuan Zhao, Hongyan Zhou, Shao Bo Su ⁎ The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

a r t i c l e

i n f o

Article history: Received 16 July 2013 Received in revised form 19 August 2013 Accepted 19 August 2013 Available online 5 September 2013 Keywords: Interleukin-1β Autoimmune diseases Biological therapy

a b s t r a c t Interleukin-1β (IL-1β) belongs to IL-1 family and is a potent pro-inflammatory cytokine. It is known to be also involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis. In addition to its pathophysiologic role in host protection, IL-1β promotes the progression of a number of autoimmune diseases. Most of such diseases can be controlled by anti-IL-1β treatment. This review discusses the contribution of IL-1β to the course of autoimmune diseases, such as rheumatic diseases, uveitis, autoimmune thyroid diseases (AITD), insulin-dependent diabetes mellitus (IDDM), autoimmune inner ear disease (AIED), multiple sclerosis (MS), myocarditis, hepatitis and kidney diseases. The critical involvement of IL-1β in the pathogenesis of autoimmune diseases provides targets for developing therapeutic treatment. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . Interleukin-1β . . . . . . . . . . . . . . . . . . Interleukin-1β and autoimmune diseases . . . . . . 3.1. Autoimmune rheumatic diseases (AIRD) . . . 3.1.1. Rheumatoid arthritis (RA) . . . . . 3.1.2. Systemic lupus erythematosus (SLE) 3.1.3. Primary Sjögren's syndrome (pSS) . 3.2. Autoimmune uveitis . . . . . . . . . . . . 3.3. Autoimmune thyroid diseases (AITD) . . . . 3.4. Insulin dependent diabetes mellitus (IDDM) . 3.5. Autoimmune inner ear disease (AIED) . . . . 3.6. Multiple sclerosis (MS) . . . . . . . . . . . 3.7. Myocarditis . . . . . . . . . . . . . . . . 3.8. Autoimmune hepatitis (AIH) . . . . . . . . 3.9. Kidney disease . . . . . . . . . . . . . . . 4. Conclusions and perspectives . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Interleukin-1 (IL-1) is a family of cytokines that play an important role in initiating the cascade of immunoinflammatory responses by ⁎ Corresponding author at: The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 S Xianlie Road, Guangzhou 510060, China. Tel.: +86 20 87330402; fax: +86 20 87330403. E-mail address: [email protected] (S.B. Su). 1567-5769/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.intimp.2013.08.012

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linking the innate and acquired immune systems [1]. IL-1 was discovered in the 1970s and was first described as lymphocyte-activating factor (LAF) stimulating both central and peripheral T lymphocytes [2,3] or leukocytic pyrogen (LP) mediating fever [4]. In human, initially, IL-1 gene family was thought to be composed of IL-1α, IL-1β and IL-1Ra which are located within 450 kb on chromosome 2q14–q21 [5]. Now it is widely believed that the members of IL-1 family consist of IL-1 agonist forms (IL-1α and IL-1β), the natural IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33, IL-36, IL-36Ra, IL-37 and IL-38 [6–11] (Table 1).

R. Zhao et al. / International Immunopharmacology 17 (2013) 658–669

Both IL-1α and IL-1β are synthesized as large precursor proteins and, whereas IL-1β is secreted, IL-1α remains in the cytoplasm or is membrane-associated and released into circulation primarily during severe diseases [12]. IL-1β precursor, the 31 kDa pro-IL-1β, is induced by activation of NF-κB pathway in response to the stimuli of pathogen associated molecular patterns (PAMPs) and localizes in the cytosol in its biologically inactive form. It is active 17.5 kDa IL-1β until cleaved by caspase-1 which is released from inflammasome in response to further stimuli of PAMPs [12–15] (Fig. 1). In resting cells, caspase-1 is in pro-caspase-1 form and binds to inflammasome that prevents its activation. Inflammasome was originally understood as a platform for the activation of caspase-1 and cleavage of the pro-forms of IL-1β and IL-18 into active cytokines [15,16]. It is now believed that inflammasome controls innate and adaptive immune responses [17,18]. It was reported that caspase-11 had also been linked to inflammasome signaling and was essential for the maturation of IL-1β by processing of pro-caspase-1 into caspase-1 [16]. IL-1β releases via a non-conventional secretion mechanism without a signal sequence [15]. In contrast to IL-1β, pro-IL-1α is biologically active and is cleaved by calpain to generate the mature protein. The amino-acid homology between human IL-1α and IL-1β is 22% and that of IL-1α to IL-1Ra is 18%; the homology of IL-1β to IL-1Ra is 26%. Hence, IL-1β is more closely related to IL-1Ra than to IL-1α. The striking difference between IL-1β and IL-1α is that both pro- and mature IL-1α can bind to their receptors and induce cellular responses, whereas pro-IL-1β is biologically inactive and requires ICE to generate the active protein. IL-1α is in acidic form while IL-1β is a neutral molecule. Furthermore, both forms of IL-1α remain intracellular and are normally found in the circulation or in inflammatory fluids unless released by a dying cell, whereas active IL-1β is secreted [19]. Because of these characteristics, more studies focus on IL-1β. In recent years, the critical role of the IL-1 family as regulators of inflammation and immunity has become apparent. IL-1 maintains a central function against infection by pathogenic organisms including bacteria [20], fungi [21] and viruses [22]. The synthesis, processing and secretion of IL-1, particularly IL-1β, are tightly regulated [22]. IL-1 affects nearly every cell either alone or in a synergistic fashion with other mediators [23,24]. IL-1β is primarily a proinflammatory cytokine to stimulate the expression of genes associated with inflammation and autoimmune diseases [25–27]. Two single nucleotide polymorphisms (SNPs) in the IL-1β gene, one at position −511 (rs16944) in the promoter region and the other in the fifth exon +3954 (rs1143634), are associated with various diseases [28]. By binding to specific highaffinity cell surface receptors, IL-1β shows pleiotropic effects that include costimulation of T lymphocytes, B cell proliferation, growth of fibroblasts, induction of adhesion molecules, stimulation of the

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production of other cytokines and inflammatory mediators in an autocrine and a paracrine way, as well as growth-inhibitory and cytocidal effect on several cell lines [29,30]. The immune system protects the host against diseases and infection. But the immune system also attacks healthy cells by mistake to cause autoimmune diseases. Autoimmune diseases affect many parts of the body. Disappointingly, the etiology of the majority of autoimmune diseases is unknown. Despite the uncertainty of the precise causes in inflammatory and autoimmune diseases, serum levels of IL-1β are elevated which correlate with disease development and severity. Clinically, the role of IL-1β has been validated by treatment of numerous diseases with anti-IL-1β treatment. Since many IL-1β-induced inflammatory diseases have been summarized in excellent reviews by other investigators, this article will focus on the current knowledge about the role of IL-1β in the pathogenic process of autoimmune diseases. 2. Interleukin-1β IL-1β exerts a range of inflammatory and immunomodulatory activities [31]. IL-1β is produced primarily by monocytes and macrophages [32] and also by T cells, NK cells, endothelial cells, fibroblasts, astrocytes, microglial cells, adrenal cortical cells [25,33] and pancreas β-cells [34]. It is a pleiotropic cytokine involved in host responses to microbial invasion, inflammation, immune regulation, metabolic reactions, hematopoietic processes and tumor progression [35]. IL-1β affects important cellular functions, such as reducing DNA content, decreasing protein synthesis and intracellular energy production, inducing β-cell apoptosis and necrosis [36]. IL-1β expression and function are tightly regulated by a complex system of IL-1 family members and their receptors. IL-1β binds to the IL-1 receptor type I (IL-1RI) expressed on all nucleated cells, which triggers the recruitment of the IL-1RAcP to form the active signaling complex. IL-1β also binds to a second receptor, IL-1 receptor type II (IL-1RII), which competes with IL-1RI for IL-1β and for the IL-1RI co-receptor, IL-1RAcP. Additionally, IL-1RII exists in both membrane bound and soluble forms (sIL-1RII) that have biological properties similar to a decoy receptor and a binding protein. The natural inhibitor IL-1Ra binds to both IL-1RI and IL-1RII, but does not allow the recruitment of IL-1RAcP [37]. IL-1β can elicit responses of the cells with a low receptor number because it activates a complex cascade resulting in signal amplification [38]. The signal transduction initiates via the 213-amino acid cytoplasmic domain of IL-1RI. The juxtaposition of the intracellular IL-1 receptor domains of IL-1RI and IL-1RAcP after IL-1β binding is necessary and sufficient for triggering intracellular signaling, which results in activation

Table 1 IL-1 family [7–11,23,37,180–187]. Chromosomal location

Expression cells

Target cells

Signaling

Regulation

IL-1α IL-1β IL-1Ra IL-18 IL-33

2q14 2q14 2q14.2 2q23.1 9p24.1

IL-1Ra, IL-1RI, IL-4, IL-10 IL-1Ra, IL-4, IL-10, DUSP1, IFN-I, 1,25(OH)2D3, matrilin-3 IL-18BP, IL-37, NF- B, CRH IFN-γ, TNF-α, IL-1β

2q12-q14.1 2q14 2q12-q21 2q14 2q12-q14.1

Mo and many cells Mo and many cells Many cells T, NK, basophils, MC, spleen cells Th2, MC, natural helper cells, basophils, eosinophils T cells, KCs, BMDCs

MAPKs, NF-κB MAPKs, NF-κB, ROCKs, AKT N/A NF-κB NF-κB

IL-36α IL-36β IL-36γ IL-36Ra IL-37

Mo, MØ, DCs and many cells Mo, MØ, DCs and many cells Mo, Neu, KCs, splenocytes MØ and DCs Epithelial and endothelial cells, fibroblasts KCs

MAPKs, NF-κB

TNF-α, Th17 cytokines

Mo, B cells, DCs, KCs MØ, Mo, epithelial cells, PBMCs, DCs

BMDCs, DCs, TH17 cells Mo and epithelial cells

N/A MAPKs, FAK, Pyk2, paxillin,

IL-38

2q13

Skin cells, B cells

T-cells, DCs

Unknown

IL-1α, IL-17A, TNF-α TGF-β1, IL-18, IFN-γ, IL-1β, TNF, CpG, IL-4, GM-CSF Unknown

Mo: monocyte; MØ: macrophage; Neu: neutrophils; DCs: dendritic cells; MC: mast cells; SMCs: smooth muscle cells; KCs: keratinocytes; PBMCs: peripheral blood mononuclear cells; BMDCs: bone marrow-derived dendritic cells; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor-κ-gene binding; FAK: focal adhesion kinase; Pyk2: proline-rich tyrosine kinase 2; C/EBP: CCAAT/enhancer-binding protein; ROCKs: Rho/Rho-associated coiled-coil forming kinases; DEC1: differentiated embryo-chondrocyte expressed gene 1; N/A: no application; GM-CSF: granulocyte-macrophage colony-stimulating factor; BMDCs: bone marrow-derived cells.

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IL-1

Stimuli 2 Stimuli 1

Extracellular

NLR / PYHIN

P I B

ASC

pro-caspase-1

NF- B Inflammasome ProIL-1 Nucleus Cytoplasm NF- B

Nuclear TranscriptIon

Fig. 1. Induction and maturation of IL-1β. IL-1β precursor is induced by activation of NF-κB pathway in response to the stimuli of PAMPs and localizes in the cytosol in its biologically inactive form. It is active 17.5 kDa IL-1β until cleaved by caspase-1 which is released from inflammasome in response to further stimuli of PAMPs.

of transcription factors (Fig. 2). The mitogen-activated protein kinase (MAPK) signal transduction pathways are activated in response to IL-1β, which are ubiquitous and regulate diverse cellular programs by relaying extracellular signals to intracellular responders. Three groups of MAPKs are activated by IL-1β: the p42 and p44 MAP kinases (also termed extracellular signal regulated kinase, ERK1, and ERK2), protein 38 MAP kinase (p38 MAPK) and the stress-activated protein kinase (SAPK, also known as the c-Jun NH2-terminal kinase, JNK) [38,39]. p38 MAPK and JNK pathways promote the stabilization of induced mRNA and regulate nuclear transcription [38,40]. MAPKs are activated by combined tyrosine/threonine phosphorylation catalyzed by MAPKK kinases (MAPKKKs) and MAPK kinases (MAPKKs), forming an evolutionarily conserved signal transduction system in Eukaryotes [41]. IL1β/IL-1RI/IL-1RAcP complex recruits intracellular adaptor proteins and kinases, including MyD88 (myeloid differentiation factor 88) and IRAKs (IL-1R associated kinases). IRAK4 phosphorylates and activates IRAK1, which further recruits TRAF6 (tumor necrosis factor receptorassociated factor 6). IRAK1 and TRAF6 complex released from the receptor complex causes TRAF6 autoubiquitination. TRAF6 is polyubiquitinated by IRAK2 as well. Ubiquitinated TRAF6 subsequently leads to the recruitment of TGF-β-activated kinase 1 (TAK1)–TAK1-binding protein 1 (TAB1)– TAB2 complex, resulting in the activation of TAK1 (a MAPKKK) then initiating MAPK cascades [38,39,42,43]. TRAF6 also catalyzes the synthesis of unanchored Lys 63 polyubiquitin chains, which bind to TAB2, leading to the activation of TAK1 directly [44]. The activated MAPKs regulate several transcription factors such as NF-κB, AP-1, and CCAAT/enhancer-binding protein (C/EBP) [45,46]. Activated TAK1 also activates transcription factors NF-κB directly. In resting cells, NF-κB combines with the regulatory protein inhibitors of κB (IκB) in the cytoplasm in an inactive form. Phosphorylation of IκB, an important step for NF-κB activation, is mediated by IκB kinase (IKK) [47,48]. Activated TAK1 activates downstream kinases IKK-α and IKK-β, which phosphorylate IκB proteins, thereby freeing NFκB which then translocates into the nucleus and binds to the target promoter to increase transcription [38,39,49]. Another kinase TNF/ IL-1-induced protein kinase (TIP/β casein kinase) also associates with

IL-1β activation cascade [50]. In addition to these pathways, IL-1β also activates the Rho/Rho-associated coiled-coil forming kinase (ROCK) pathway associated with the remodeling of actin filaments [43]. The complex cascade of IL-1β signaling contributes to the development and progression of various diseases. 3. Interleukin-1β and autoimmune diseases The IL-1 receptor-bearing cells are extremely sensitive to IL-1 and the overproduction of IL-1 often leads to serious disorders [6]. Absence of IL-1Ra expression during an immune response, or other molecules that oppose the IL-1β inflammatory cascade, promotes the development of autoimmune diseases [51]. The widespread distribution of IL-1β and imbalanced IL-1β and IL-1Ra ratio in serum or tissue have been implicated not only in altered susceptibility to infections but also in other conditions such as autoimmune diseases, as exemplified in the following sections. 3.1. Autoimmune rheumatic diseases (AIRD) Autoimmune rheumatic diseases (AIRD) are a category of refractory diseases based on their ambiguous pathogenesis. Rheumatoid factor, antinuclear antibodies and anti-neutrophil cytoplasmic antibodies are key parameters in the diagnosis of AIRD. Among AIRD, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren's syndrome (pSS) are the most common diseases and have received particular attention by physician and basic researchers [31,52]. 3.1.1. Rheumatoid arthritis (RA) Rheumatoid arthritis (RA) is an autoimmune systemic disease characterized by persistent inflammation of the diartrodial joints with synovial hyperplasia and progressive joint destruction [31]. The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of RA [53].

R. Zhao et al. / International Immunopharmacology 17 (2013) 658–669

IL-1Ra IL-1RI

IL-1 β

IL-1 β

IL-1RI

IL-1RII

AcP

Extracellular matrix

661

No signal

MyD88 No signal IRAK4 IRAK1

IRAK1

P

TRAF6

TRAF6

TAB1 IκB α

TAB2

Ub Ub

P

NF- κB

IκB α

P IKK- α

NF- κB

IKK- β

TAK1

TAK1

MEK1/2

MKK3/6

MKK4/7

ERK1/2

p38 MAPK

SAPK/ JNK1,2,3

Cytoplasm

Nucleus Nuclear TranscriptIon

mRNA Stabilization

Fig. 2. IL-1β signaling pathway. Matured IL-1β/IL-1RI/IL-1RAcP complex recruits MyD88 and IRAKs. IRAK4 phosphorylates and activates IRAK1, which further recruits TRAF6. IRAK1 and TRAF6 complex released from the receptor complex causes TRAF6 autoubiquitination. Ubiquitinated TRAF6 subsequently leads to recruitment of the TAB1–TAB2 complex, which results in the activation of TAK1 to initiate the cascades of ERK1/2, p38 MAPK and JNK which regulate nuclear transcription. p38 MAPK and JNK enhance the stabilization of mRNA as well. Activated TAK1 also stimulated downstream kinases IKK-α and IKK-β, which phosphorylate IκB, thereby freeing NF-κB which then translocates into the nucleus and binds to the target promoter to increase transcription.

In the pathogenesis of RA, cytokines contribute to the activation of fibroblast-like synoviocytes (FLS) that leads to erosion of cartilage and bone [54]. It is believed that TNF-α, IL-1β and IL-6 are primary cytokines involved in the progression of chronic joint inflammation and the concomitant erosive changes in cartilage and bone [55–57]. As the cytokine derived from synovial membrane, IL-1β is pivotal in initiating cartilage erosion [54,58,59]. Serum and synovial concentrations of IL-1β are higher in RA patients with active disease than in those in remission [31,60]. Furthermore, cartilage from arthritis patients contains upregulated IL-1β mRNA [59]. Numerous observations have shown that tissue destruction and the resulting disability of RA patients are partly the result of extracellular matrix degradation by proteolytic enzymes including matrix metalloproteinases (MMPs) and the release of the mineral phase (Ca2 + release) by prostaglandin E2 (PGE2) [19]. IL-1β triggers the expression of MMP genes such as collagenases and elastase, stimulates the secretion of PGE2 and several proinflammatory mediators involved in joint destruction, and induces the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-l) by synovial cells [31,61]. MMPs, induced

by IL-1β, degrade all components of the extracellular matrix. The collagenases, MMP-1 and MMP-13, have predominant roles in RA because they are rate limiting in the process of collagen degradation [19]. IL-1β induction of MMP-1 requires pathways different from those required by induction of MMP-13. MMP-1 induction depends on p38 and MEK, while p38, JNK, and NF-κB are required for induction of MMP-13 by IL-1β [62]. IL-1β potently induces MMP-13 by activation of p38 MAPK pathway, transcription factor AP-1 and the tissuespecific Runx-2 [63]. IL-1β-activated AP-1 binds to an evolutionarily conserved DNA sequence ∼ 20 kb upstream relative to the MMP-13 transcription start site (TSS) [64]. Understanding of RA pathophysiological mechanisms has led to the development of a new therapy designed against more precise targets involved in disease course. The side effects and/or poor efficiency of traditional pharmacological therapies (non-steroidal antiinflammatory drugs, NSAIDS and disease-modifying anti-rheumatic drugs, DMARDS) for RA prompted the development of anti-cytokine strategies. Targeting pathways triggered by IL-1β may provide a promising therapeutic opportunity for RA. IL-1Ra has been proven effective in the treatment of

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RA patients [31,65–67]. Anakinra, a recombinant, nonglycosylated human IL-1Ra, is a relatively safe and modestly efficacious therapeutic agent for RA. Anakinra shows down the progression of radiographic joint damage [68]. Anakinra is originally developed for the treatment of moderate–severe RA that has been unresponsive to initial DMARD therapy [69]. It is recommended for the treatment of active RA after an adequate trial of another conventional DMARD, alone or with methotrexate (MTX) [70–72]. Biological therapy with Anakinra in RA has been approved by the US Food and Drug Administration (FDA) in clinical phase IV trial. However, 30% RA patients showed no response to IL-1Ra treatment and the responses were highly variable from one patient to another [55]. Targeting IL-1β with specific antibodies has also shown benefit for the treatment of RA. Gevokizumab (XOMA 052, a recombinant humanized anti-IL-1β antibody) was effective in preventing and treating joint inflammation, at lower and less frequent doses than Anakinra. It was hypothesized that XOMA 052 may have increased efficacy for RA treatment due to its higher affinity for IL-1β and longer halflife in vivo [73]. 3.1.2. Systemic lupus erythematosus (SLE) SLE is a systemic autoimmune disease characterized by increased production of autoantibodies against a relatively limited range of nuclear antigens. The dysregulated immune system produces autoantibodies resulting in the formation of immune complexes that deposit in tissues, thereby attacking the skin, joints, kidneys, heart, and brain [74]. Cytokines are essential for the control of the specific immune responses that characterize SLE [75]. IL-1 is crucial for the synthesis of IgG autoantibodies in patients with SLE [76]. High levels of IL-1 in the course of SLE have been documented [75,77,78]. Although the role of IL-1β in SLE has not been fully defined, there is evidence that IL-1β secretion by PBMC is higher in patients with SLE [79]. Enhanced steady state levels of mRNA for TNF-α and IL-1β, but not IL-1α, have been detected in the renal cortices of animals with lupus nephritis. It was hypothesized that TNF and IL-1, especially IL-1β, contribute to nephritis in murine models of lupus [80]. The importance of secretable IL-1β, rather than cell-associated IL-1α, in the immunostimulatory and inflammatory responses that mediate the pathogenesis of experimental SLE has been suggested [81]. IL-1 receptor-associated kinase 1 (IRAK1) is part of the IL-1/Toll receptor and NF-κB signaling pathway and has been associated with the onset of SLE [82]. In a cross-sectional study, increased serum concentration of IL-1Ra is a pathophysiologic feature of active SLE [83]. Lower levels of IL-1Ra have also been detected in lupus nephritis and coincide with kidney involvement in SLE [31,84]. Thus, high concentrations of IL-1Ra were restricted to patients with extra-renal disease and serum levels in patients with kidney involvement were low or only moderately increased [84]. These data add further evidence for the IL-1β cascade involvement in the pathogenesis of SLE. It has been reported that IL-1β polymorphism influences the susceptibility to acquire SLE and IL-1β +3953 allele was protective from SLE [31]. Mice deficient in IL-1β produce lower levels of antidouble-stranded DNA (anti-dsDNA) antibodies, characteristic of SLE and central to the diagnosis of the disease. Overall, disease severity was milder in mice deficient in IL-1β. Thus, IL-1β is an important factor in the induction and pathogenesis of experimental SLE [81]. Anakinra might be an interesting therapeutic alternative for individual patients with SLE not responding to conventional treatment [85]. Anakinra has been shown to be safe and effective in improving arthritis in a trial of four SLE patients. Therefore, targeting the IL-1β pathway provides a therapeutic opportunity for SLE. 3.1.3. Primary Sjögren's syndrome (pSS) Sjögren's syndrome may exist as a primary disorder (primary Sjögren's syndrome) or be associated with other autoimmune diseases (secondary Sjögren's syndrome) such as RA, SLE, or systemic sclerosis [86,87]. pSS is characterized by chronic lymphocytic or mononuclear cell infiltration near epithelial cells of exocrine glands and the presence

of anti-Ro/SSA and anti-La/SSB antibodies associated with glandular dysfunction [88,89]. In the disease process, lacrimal and salivary glands are affected and keratoconjunctivitis sicca and xerostomia appear. Although the pathophysiology of pSS is not yet fully understood, there is evidence that IL-1β, TNF-α and IL-6 are important mediators of the autoimmune responses and may cause tissue destruction in salivary and lachrymal glands [90,91]. High levels of IL-1 β in parotid acinar and lacrimal gland cells in mouse model or patients with Sjögren's syndrome have been detected [92,93]. IL-1β is also secreted by peripheral blood mononuclear cells (PBMC) from patients with pSS [88,94]. The abnormal local and systemic production of IL-1β suggests a pathogenic role of IL-1β in pSS. Exogenous addition of IL-1β inhibits neurotransmitter release and lacrimal gland protein secretion [86]. Evidence also suggests that IL-1β may be involved in the destruction of salivary and lacrimal glands in SS [95]. IL-1β may have a proteolytic activity for degradation of the basement membrane and leads to the disruption of acinar or ductal structure in salivary glands [90]. It has been shown that IL-1β inhibits neurotransmitter release in the lacrimal gland resulting in impaired protein secretion and dry eye [96]. The iNOS is known to be induced in the presence of pro-inflammatory cytokines in several secretory epithelial cell types. Lacrimal gland acinar cells are able to produce iNOS and NO in response to IL-1β. This pathway of iNOS induction and overproduction of NO may be a factor in lacrimal gland cell death, a significant pathophysiological pathway of dry eye syndrome [92]. In addition, IL-1β-induced MMP-9 expression and corneal cell migration were mediated through the p42/p44 MAPK- and JNK1/2-dependent AP-1 and NF-kB pathways resulting in dry eye. IL1β causes marked p42/p44 MAPK translocation from the cytosol into the nucleus in corneal cells with yet an unknown mechanism [39]. In addition, IL-1β gene polymorphisms may affect the susceptibility to pSS [95]. The efficacy of an IL-1Ra, Anakinra, is currently studied in a short-term placebo-controlled trial in pSS and may be a potential treatment of pSS [97]. 3.2. Autoimmune uveitis Uveitis is an umbrella term for intraocular inflammation of a variety of etiology. There are numerous causes for uveitis including infection, systemic autoimmune disorders and mechanical injury. The classic autoimmune uveitis includes Behçet's disease (BD), sarcoidosis and Vogt–Koyanagi–Harada (VKH) disease. The initiating factors for uveitis are not well understood. Experimental autoimmune uveitis (EAU) serves as an animal model for the study of human chronic uveitis induced in Lewis rats or mice by immunization with S-antigen or interphotoreceptor retinoid-binding protein (IRBP). Endotoxininduced uveitis (EIU) is an animal model for acute ocular inflammation induced by injection of LPS. Recent studies in mice and with human cells showed that IL-1β was essential for the development of Th17 cells [98], which are increasingly recognized as the key effector cells responsible for autoimmune uveitis [99,100]. IL-1 gene cluster polymorphisms, including IL-1A and IL-1B genes, are associated with an increased risk for Behçet's disease [101]. In addition, IL-1β participates in the pathogenesis of autoimmune uveitis [102,103], and it is effective to use IL-1Ra or anti-IL-1β antibody for treatment [104–106]. NF-κB, activated by IL-1β, plays an important role in the development of EAU and EIU [107]. It has been reported that NF-κB inhibitor, STA-5326, is a promising therapeutic modality for refractory uveitis in human [107]. Kitamei et al. showed several efficacious NF-κB inhibitors on EAU [108]. Acute uveitis was ameliorated by inhibition of IκB kinase β (IKKβ) in rats, particularly when the disease was induced by IL-1β and TNF-α [109]. IL-1β expression was promoted by NF-κB and IL-1β in turn activates IKK. This positive regulatory loop amplifies local inflammatory responses [108]. Ugurlu et al. described a patient with juvenile Behçet's syndrome whose diseased eye was refractory to conventional immunosuppressive agent and corticosteroids. But the patient was treated

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successfully with a single dose of Canakinumab, a human antiinterleukin-1β antibody [110,111]. Interestingly, the patient did not respond to Anakinra, IL-1Ra that blocks both IL-1α and IL-1β. This may imply a predominance function for IL-1β on uveitis. 3.3. Autoimmune thyroid diseases (AITD) Thyroid auto-immunity is clinically divided into two major subtypes, with over functioning (hyperthyroidism: Graves' disease (GD)) or under functioning (hypothyroidism: Hashimoto thyroiditis (HT)) of the gland. During the development of autoimmune thyroid diseases (AITD), environmental factors, immune system and target tissue are simultaneously involved [112]. Proinflammatory cytokines such as IL-1β and TNF-α are known to affect thyroid function by stimulating IL-6 secretion and modifying epithelium integrity and altering junction proteins such as ZO-1, Claudin and JAM-A. The expression, localization and organization of junction proteins that ensure the epithelial barrier function in the thyroid tissue of patients with AITD (HT and GD) are altered. Therefore, IL-1β modifies thyroid epithelial tightness of human thyrocytes through altering the expression and localization of junction proteins [113]. Paolieri et al. [114] demonstrated that IL-1β was the only cytokine able to induce both Fas expression on Fas-negative thyroid follicular cells (TFC) and B7.1. Fas/Apo1/CD95, an important participant in apoptosis, and B7.1, a member of a family of “co-stimulatory” molecules crucial for efficient antigen presentation, are two additive surface functional molecules of TFC from HT patients. IL-1β induces the tissue damage via suicide Fas/FasL-mediated TFC interaction and the perpetuation of autoimmune reaction via co-stimulatory molecules. Therefore, IL-1β plays a crucial role in the pathogenesis of thyroid autoimmunity. The thyroid dysfunction in GD can be treated effectively. However no reliable, specific, and effective medical therapies have yet been developed for thyroid-associated ophthalmopathy (TAO) [115]. TAO, an autoimmune component of Graves' disease, encompasses specifically to the orbital and periorbital manifestations [115]. It is the most common orbital disease in adults also called Graves' ophthalmopathy (GO) or thyroid eye disease [116]. TAO is associated with profound connective tissue remodeling and fibrosis that appear to involve selective activation of orbital fibroblasts with aberrant accumulation of extracellular matrix molecules glycosaminoglycans (GAGs) in retro-ocular tissue [117]. GAGs then in turn are responsible for the development of clinical signs and symptoms. Oxygen free radicals which are induced by IL-1β are involved in GAG accumulation [118]. Recently, Han et al. demonstrated that orbital fibroblasts treated with IL-1β expressed high levels of tissue inhibitor of metalloproteinase-1 (TIMP-1). The effect of IL-1β was at the pretranslational level and involves elevating the TIMP-1 gene promoter. TIMP-1 is an important modulator of matrix metalloproteinase (MMP) activity. Thus, the important balance between MMPs and TIMPs in human orbit may become disrupted in TAO and that results in fibrosis. IL-1β activates ERK1/2 pathway in fibroblasts and interrupting the pathway with PD98059, a chemical inhibitor of MEK, or by transfecting cells with a dominant negative ERK 1 plasmid results in the attenuation of TIMP-1 induction [117]. Thus, anti-IL-1β treatment may represent an important therapy for modifying the proteolytic environment and restore natural tissue remodeling in TAO. In addition, IL-1β decreases tear production by lacrimal gland [96]. IL-1β, IL-6, and IL-8 concentrations in tears were significantly higher in active TAO than in inactive TAO patients and controls. There was a positive correlation between tear IL-1β, IL-6 and IL-8 levels and clinical activity score (CAS) in TAO patients [119]. 3.4. Insulin dependent diabetes mellitus (IDDM) Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by lymphocytic infiltration of the pancreatic islets (insulitis) and the presence of islet cell autoantibodies [120].

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Proinflammatory cytokines released as part of the insulitis process have been implicated as effector molecules that participate in both islet inflammation and beta-cell lesion during the development of IDDM [121]. A possible diabetogenic effect of cytokines may be mediated by their induction of abnormal expression of islet cell autoantigens. In all stages of IDDM higher levels of IL-1β and TNF-α were detected in patient serum [122]. IL-1β, together with IFN-γ and TNF-α, mediates pancreatic β-cell destruction and death [36,123–126]. It is demonstrated that IL-1β induces β-cell damage by a NO-mediated mechanism [127]. Pancreatic β-cells are more sensitive to IL-1β than to other NO donors [36]. The synthesis of both isoforms of islet enzyme glutamate decarboxylase (GAD), GAD65 and GAD67, is decreased in the presence of IL-1β. GAD is a major target of β-cell autoimmunity in IDDM and IL-1β is the primary cytokine affecting GAD-65 expression [128,129]. In addition, activation of the transcription factor NF-κB is necessary for cytokine-induced pancreatic β-cell death. IL-1β induces NF-κB activation and has a more pronounced pro-apoptotic effect than TNF-α [130–132]. Wilson et al. reported that in the administration of a high dose IL-1β accelerated the onset of IDDM compared to saline-injected controls, while in a low dose IL-1β significantly reduced the frequency of IDDM compared to placebo and high dose IL-1β treatment groups. The results demonstrate that exogenous administration of IL-1β affects rat idiopathic autoimmune diabetes in a dose-dependent manner [133]. Cailleau et al. showed that treatment with neutralizing antibodies for IL1β prevented cyclophosphamide-induced diabetes in nonobese diabetic mice [134]. Whether control of inflammatory pathways mediated by IL-1β using the recombinant IL-1Ra Anakinra will yield measurable decreases in the expression of genes that are otherwise overexpressed as a consequence of IL-1β effect in diabetes requires further investigation. It is believed that control of IL-1β pathways will be benefit the preservation of insulin secretory capacity [135]. A phase I therapy with Rilonacept, a soluble decoy receptor, in adolescents and adults with IDDM is ongoing. These observations support the inhibition of IL-1β may limit the immune responses and reduce the rate of β-cell destruction in IDDM. 3.5. Autoimmune inner ear disease (AIED) Autoimmune inner ear disease (AIED), originally defined as autoimmune sensorineural hearing loss, is an inscrutable disorder. It is characterized by recurring episodes of sudden or progressive sensorineural hearing loss and bilateral sensorineural hearing loss. The disease responds to treatment by immunosuppressives, and occurs in people between the ages of 30 and 60 years [51,136,137]. Patients with AIED usually experience multiple episodes of rapid hearing loss either concurrently or sequentially in both ears. Of those with AIED, up to 30% may have a systemic autoimmune disease such as Cogan syndrome, Wegener granulomatosis, SLE, and various systemic vasculitides [138]. For patients who experience an acute, sensorineural decline in hearing, timely corticosteroid administration may result in preservation of some or all of the hearing. Corticosteroids are widely used in the treatment of AIED and have been the standard treatment for the disease. Unfortunately, not all patients respond to the steroids, and in responders, some develop resistance over time. To date, no effective treatment has been identified for patients with either AIED who do not respond to steroids. Recently, treatment for corticosteroid non-responders with Anakinra is effective and resulted in reduction in IL-1β release, suggesting that IL-1β blockade may be a choice of therapy for these patients. Pathak et al. [51] demonstrated that circulating plasma levels of IL-1β in corticosteroid non-responders are higher as compared with corticosteroid-responders. IL-1β and MMP-9 are overexpressed in PBMC of corticosteroid resistant AIED patients but dexamethasone fails to regulate the expression of these proteins. Treatment of corticosteroid non-responders with Anakinra resulted in the inhibition of IL-1β and MMP-9 release. IL-1β has the ability to induce MMP-9 expression, which cleaves IL-1RII and then enhances IL-1β-induced signal pathway. Therefore, a greater capacity of Anakinra

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to reduce MMP-9 expression in nonresponders than responders may be due to a reduction of circulating IL-1β. Thus, IL-1β may play a pivotal role in corticosteroid non-responder AIED. Nevertheless, the exact mechanism of AIED and how IL-1β participates in the progression of this disease remain uncertain. Research is required to delineate the pathophysiologic mechanisms. 3.6. Multiple sclerosis (MS) Multiple sclerosis (MS) is a chronic inflammatory disease mediated by activated T cells, B cells and monocytes (MO), with an autoimmune origin [1]. It is characterized by an altered balance between cytokines followed by selective destruction of myelin and gliosis in the central nervous system (CNS) [139,140]. Experimental autoimmune encephalomyelitis (EAE) is a mouse chronic demyelinating disease model for MS. Filion et al. reveal that MO secreted significant levels of proinflammatory/regulatory cytokines, specifically IL-1β, IL-6 and TNFα, in MS patients as compared to healthy individuals [140]. T effector cells can cause CNS inflammation and demyelinating lesions [141] and IL-17 is important in the immunopathogenesis of autoimmune demyelinating disease [142]. IL-1β is essential for the development of Th1 and Th17 cells [98,143]. Studies showed increased levels of IL-1β in the cerebral spinal fluid (CSF) and sera of MS patients. High levels of IL-1β have also been observed in MS brain lesions while IL-1β has been rarely demonstrated in normal CNS tissue [144]. Huitinga et al. suggested that IL-1β produced by activated glial cells in the hypothalamus of MS patients may contribute to the activation of the hypothalamic CRH neurons, while reduced expression of neuronal IL-1β in MS patients may have consequences for neuroendocrine, behavioural or autonomic functioning [145]. Rats with active EAE, treated with human recombinant IL-1Ra, during the induction phase of disease, developed milder signs of EAE [146]. Circulating serum levels of IL-1Ra are normal during the remission phase of relapsing–remitting MS, but it increases significantly during exacerbation or in response to interferon-β treatment [147]. Therefore, IL-1Ra has a therapeutical potential for MS during exacerbation. Dujmovic et al. revealed that IL-1Ra and/or IL-1RII were increased in the sera after steroid treatment for relapsing MS and suggest the important role of IL-1β. Thus, induction of IL-1RII and IL-1Ra in MS may be beneficial [1]. The production of IL-1 by peripheral blood mononuclear cells (PBMCs) was assessed in patients with relapsing MS in both the active and inactive phases and in chronic progressive MS patients. IL-1α production was significantly higher in MS patients than in healthy subjects while IL-1β in MS patients was not significantly elevated [148]. Therefore, the role of IL-1β in MS needs further research. 3.7. Myocarditis Myocarditis is a major cause of heart failure and sudden death in adolescents and young adults. Autoimmunity plays an important role in myocarditis, in particular, a reaction to cardiac myosin following viral infection may contribute to the development of myocarditis [149]. Experimental autoimmune myocarditis (EAM) is an animal model of human giant cell myocarditis, characterized by extremely severe myocardial damage and the appearance of multinucleated giant cells [150]. One of the leading causes of autoimmune myocardial lesion in patients with myocarditis is imbalance between pro-inflammatory and antiinflammatory cytokines [151]. IFN-γ, IL-1β, and TNF-α have been reported to possess negative inotropic effects against the myocardium and directly cause myocarditis through induction of NO [152]. Rose et al. found that increased production of IL-1β and TNF-α during the early innate response to virus infection is necessary and sufficient to induce a later heart-specific autoimmune disease [153]. Circulating IL-1β and TNF-α, which activate cytotoxic reactions, are markedly increased in patients with myocarditis [151,154,155], and the levels of IL-1β and TNF-α are correlated with the severity of the disease [156]. Inhibition

of these cytokines can prevent the development of EAM [155–157]. IL-1β has multiple effects on cardiac function. In patients with myocarditis myocardial contractility is depressed. Stein et al. demonstrated that IL-1β has direct negative inotropic effects on cardiomyocytes which may lead to the contractile dysfunction [158]. In synergy with TNF-α, IL-1β considerably enhances collagen synthesis and production of MMP 2 and MMP 9, two matrix metalloproteins that are associated with cardiac remodeling [153]. IL-1β activates NF-κB which in turn increases IL-1β transcription to cause myocardial damage in EAM [159]. These results suggest that IL-1β is a significant cytokine in the pathogenesis of myocarditis and blockade of IL-1β may be a treatment. 3.8. Autoimmune hepatitis (AIH) Hepatitis is an inflammation of the liver and can be caused by one of many factors including microbial infection, liver injury by toxins, and attack by host immune system. Autoimmune hepatitis (AIH) is a chronic inflammatory disorder of unknown etiology characterized by periportal inflammation, increased serum aminotransferase, hypergammaglobulinemia, circulating autoantibodies, and a remarkable response to immunosuppressive therapy [160,161]. Cytokines are thought to play a central role in liver metabolism and in the immune responses to viral components. IL-1β production is an important initiating factor in the cascade of events resulting in liver inflammation [30]. IL-1β and IL-6 genes are expressed in the liver infected by HBV, either chronically or acutely, with the exception of fulminant HBV hepatitis [162]. IL-1β is significantly elevated in the serum or within the liver of patients with hepatitis [30,163,164]. Gramantieri et al. found a mild reduction in the IL-1β/IL-1Ra ratio in minimal/mild chronic active hepatitis (CAH) and a strong increase in moderate/severe CAH [30]. ICAM-I is one of cell-surface molecules which mediates the interaction between hepatocytes and cells of the immune system [165]. Circulating levels of ICAM-I are significantly elevated in patients with various autoimmune liver diseases with low or undetectable levels in normal tissues. Inhibition of tissue ICAM-I expression and reduction in sICAMI levels may be important consequences of the actions of various treatments with immunosuppressive agents [165–167]. Incubation with inflammatory cytokines (IL-1β or TNF-α combined with IFN-γ) showed an increase in ICAM-I RNA levels in hepatocytes [165]. Th0 lymphocytes differentiate into Th1 or Th2 cells, while IL-1β and IL-6 favor differentiation into Th17 cells which have been demonstrated to play an important role in the pathogenesis of AIH [160,168]. Geneva-Popova M et al. suggest that IL-1β, IL-6 and TNF-α exist at high levels in the sera of patients with a self-limited form of acute hepatitis B infection (A-HBV). Their data indicate that these cytokines may be related either to multiple immune abnormalities or to favorable outcome of the disease [169]. Furthermore, IL-1β may directly target IFN-αβ signaling in hepatocytes, which are the only established treatment for viral hepatitis. Attenuation of IFN-αβ signaling in the liver by IL-1β could be one of the mechanisms underlying the resistance to IFN therapy [164]. 3.9. Kidney disease Cytokines such as IL-1β, IL-6 and TNF-α contribute to the progression of many kidney diseases and are associated with the development of common chronic kidney disease (CKD) complications [170–172]. The capacity of LPS-stimulated isolated erythrocyte-perfused rat kidney (IEPK) to produce monocyte chemoattractant protein-1 (MCP-1), IL-1β, and TNF-α mRNA has been demonstrated [173]. Both MAPKs and NF-κB are involved in the pathological conditions in the kidney, and are triggered by IL-1β. Thus, IL-1β plays an important role in kidney diseases by increasing MAPK and NF-κB signaling. The influence of cytokine gene polymorphisms on various immunologic complications after solid kidney transplantation is evaluated [174]. Kidney transplant recipients of the IL-1β-511CC genotype are at higher risk for the onset of

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Table 2 The role of IL-1β in autoimmune diseases [31,51,54,62,74,86,88,90,95,98,107,113,114,117,118,123,139,145,150,158,161,164,175]. Disease

Pathological process

The role of IL-1β

RA SLE pSS

Activation of FLS, erosion of cartilage and bone Multisystem inflammation with the generation of autoantibodies Lym or Mon infiltration to epithelial cells of exocrine glands and dryness of the eyes and mouth Autoreactive T-cells to destroy photoreceptor cells in retina Lym infiltration and the presence of autoantibodies of the thyroid gland and developed thyroid tissue destroyed Tissue remodeling and fibrosis; accumulation of GAG in retro-ocular tissue Lym infiltration and the presence of autoantibodies of the pancreatic islets Antibodies or immune cells which are attacking the inner ear Selective destruction of myelin and gliosis in CNS Myocardial damage and the appearance of MGCs Periportal inflammation, increased serum aminotransferase, hypergammaglobulinemia, circulating autoantibodies Abnormal buildup of Ig and the presence of autoantibodies against the kidney

Expression of MMPs, adhesion molecules and proinflammatory mediators Susceptibility to acquire SLE Degradation of the basement membrane, disruption of acinar or ductal structure in salivary glands, induced iNOS Th1/17 cell differentiation, activates NF-κB Enhances IL-6 secretion and modifies epithelium integrity, induces Fas expression and the tissue damage Involves in GAG accumulation, induces TIMP-1 Mediates β-cell destruction and death through NO Induces MMP-9 expression Th1/Th17 cell differentiation, activates the hypothalamic CRH neurons Exacerbates cardiac myocyte remodeling and myocardial damage Increases ICAM-I RNA, favors Th0 Lym differentiation into Th17 cells, targets IFN-αβ signaling Higher risk for the onset of infection after kidney transplantation

Uveitis AITD TAO IDDM AIED MS Myocarditis AIH Kidney diseases

FLS: fibroblast-like synoviocytes; GAG: glycosaminoglycans; TIMP-1: tissue inhibitor of metalloproteinase-1; ICAM-l: intercellular adhesion molecule-1; MGCs: multinucleated giant cells; MMP: matrix metalloproteinase.

infection after kidney transplantation [175]. In addition, Wan et al. showed that recipients with IL-1β-511CC genotype or IL-1β-511C allele were more prone to the development of bacteremia within the first year after kidney transplantation [176]. Neutrophil recruitment induced by IL-1 β-stimulated chemokines is likely to play a key role in the disease and may provide novel therapeutic targets for acute tubular necrosis (ATN) [177]. 4. Conclusions and perspectives IL-1β participates in nearly all autoimmune diseases. There are complicated mechanisms for IL-1β to contribute to these diseases (Table 2). Because of the synergistic, and in some cases, redundant effects of many other proinflammatory cytokines such as TNFα and IL-6, it is expected that effective treatment of autoimmune diseases will require simultaneous inhibition of multiple cytokines. Combination therapy based on IL-1β may prove to be beneficial in curing many immunological disorders. In addition, DNA vaccines targeting IL-1β have been considered as good candidates for eradicating or alleviating autoimmune diseases [178]. It has been demonstrated that decreased production of IL-1β in patients with autoimmune disease leads to immune defects. Therefore, development of an efficient IL-1 inhibitor for clinical use is of importance. Clinical trials using recombinant IL-1 blocking agents are ongoing. Currently four IL-1β targeted agents have been approved by FDA: IL-1Ra Anakinra (Kineret, blocks both IL-1α and IL-1β), the neutralizing monoclonal antibody Canakinumab (specifically targets IL-1β) and Gevokizumab (XOMA 052, a recombinant humanized

anti-IL-1β antibody), the soluble decoy receptor rilonacept (binds IL-1β N IL-1α N IL-1Ra) [106,110,179] (Table 3). Other therapeutic approaches, including a monoclonal antibody directed against the IL-1 receptor and orally active small molecules that target the release of active IL-1β, have also been developed [179]. Anakinra has a half life of 4 to 6 h with a FDA approved recommended dose of 100 mg/day subcutaneously for the treatment of RA. Phase 1 clinical trials evaluating the safety and pharmacokinetics (PK) of Gevokizumab administered to patients with active, stable, moderate to severe RA have been completed. FDA grants orphan drug status to Gevokizumab in August 2012 and its safety and efficacy in the treatment of active non-infectious intermediate, posterior, or pan-uveitis clinical trials are in phase 3 trial. Anakinra may be able to treat BD with fewer side effects. Phase 2 clinical trials are projected to complete in August 2013. Clinical trials of the effect of Anakinra on insulin production in patients with new onset type 1 diabetes are in phase 3 trial and therapy in children with newly diagnosed type 1 DM (by ADA criteria) in phase 2 is underway. Gevokizumab may inhibit beta-cell destruction and enhance beta-cell regeneration. The effects of Gevokizumab on insulin production and β cell function in subjects with well-controlled type 1 diabetes in phase 2 trial are ongoing. A phase 1 open label clinical trial of Anakinra for corticosteroid-resistant patients is ongoing to determine if this therapy may improve hearing thresholds in patients with AIED. The clinical trials of IL-1Ra in chronic kidney disease and cardiovascular disease also have begun. Although these inhibitors have shown efficacy in a number of diseases, new therapeutic options with more potent inhibitors need development.

Table 3 Anti-IL-1 β therapy. (Reference: http://www.clinicaltrials.gov/).

IL-1Ra (Anakinra)

Human monoclonal IL-1β antibody (Canakinumab) Humanized IL-1β antibody (Gevokizumab)

Decoy receptor (Rilonacept)

Disease

Effect of therapy

Clinical trial

RA IDDM pSS AIED MS SLE RA BD IDDM RA AIED Uveitis IDDM IDDM

Retards the progression of radiographic joint damage; effective to moderate–severe RA Insulin production Be a potential strategy for future treatment Improves hearing thresholds Therapeutic effect during exacerbations Safety and efficacy in improving arthritis in SLE patients Retards the progression of radiographic joint damage Safety and efficacy Therapeutic intervention of IDDM Prevents and treats joint inflammation Reduces MMP-9 expression Treats successfully Inhibits β-cell destruction and enhances β-cell regeneration Slows the loss of the body's ability to secrete insulin

Phase 4 Phase 3 None Phase1/2 None None Phase 2 Phase 2 Phase 2 Phase 2 None Phase 3 Phase 2 Phase 1

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