Anti-IL-1 molecules: New comers and new indications

doi:10.1016/j.jbspin.2009.10.011

Joint Bone Spine

Volume 77, Issue 2, March 2010, Pages 102-107

https://doi.org/10.1016/j.jbspin.2009.10.011 Get rights and content

Abstract

The interleukin 1 family is composed by the interleukin 1 (IL-1) and its natural occurring inhibitor, the interleukin 1 receptor antagonist (IL-1Ra). The role of both molecules in rheumatoid arthritis has been widely established, and in this sense new molecules blocking IL-1 actions are under investigation. Anakinra is the recombinant form of IL-1Ra, and has proven to be well tolerated and indicated in the treatment of rheumatoid arthritis. Nevertheless, other molecules such as mAb anti-IL-1 and IL-1 Trap are being developed. Moreover, the recent relation of IL-1 in the inflammasome and pathways of innate immunity has lead to new indications of anti-IL-1 molecules, especially in the autoinflammatory syndromes as well as in other inflammatory diseases. Herein we have performed a review of the literature, limited to English language journals (PUBMED search: combination of descriptors IL-1 and anakinra, systemic juvenile idiopathic arthritis, adult's onset Still's disease, autoinflammatory syndromes, gout, pseudogout, ankylosing spondylitis, and systemic lupus erythematosus from January 1985–December 2008) emphasizing the possible new indications. Although sufficient data is not yet available to fully assess the efficacy and safety of anti-IL-1 molecules in patients with inflammatory disorders other than rheumatoid arthritis, new data is promising.

Introduction

Interleukin 1 (IL-1) is a proinflammatory cytokine and its role in the inflammatory response has been well established. It has been implicated in the pathogenesis of several chronic diseases, including rheumatoid arthritis (RA), and until today anti-IL-1 molecules are a valid therapy for refractory RA.

Nevertheless, the recent implication of IL-1 in the inflammasome and the NALP receptors opens a new lead of investigation. NALP3 mutations are thought to be responsible for a group of diseases called autoinflammatory syndromes through an abnormal activation of the inflammasome leading to an excessive IL-1 production. More recently, IL-1 has also been implicated in the inflammatory cascade of the acute gout and pseudogout attack via the NALP3-inflammasome. Those recent findings have lead to explore new therapeutical roles for anti-IL-1 molecules.

Section snippets

Interleukin 1 family

IL-1 is a major inflammatory mediator and exists in two forms: IL-1α and IL-1β. Each form is the product of two separate genes, but is related to each other structurally at a three-dimension level. Mononuclear cells, primarily monocytic phagocytes synthesize both IL-1 [1].

Biological actions of IL-1

The biological effects of IL-1α and IL-1β [2] have been reviewed in detail, particularly in the areas of IL-1 effects on the hypothalamic-pituitary-adrenal axis [4] bone metabolism [5], in the pathogenesis of RA and loss of lean body mass [6].

Systemic injection of recombinant IL-1 elicits fever, anorexia, hypotension, leucopenia and thrombocytopenia. IL-1 stimulates production of acute phase proteins by the liver, including IL-6, fibrinogen, complement components, and various clotting factors.

Biological actions of IL-1Ra

Secreted IL-1Ra is an inducible gene in most cells, but intracellular IL-1Ra is expressed constitutively in keratinocytes and intestinal epithelial cells. IL-1Ra represents the first naturally occurring cytokine or hormone-like molecule acting as a specific receptor antagonist.

Many experiments have tried to elucidate the biological properties of IL-1Ra over the past years, and no unequivocal agonists effects have been reported so far. Natural sIL-1Ra is a 22-kD glycosylated protein, but the

IL-1 Inhibition: new comers

The role of IL-1 in various disease animal models has been inferred by the protective effects of recombinant IL-1Ra, soluble IL-1 receptors and neutralizing antibodies to IL-1-α and IL-1β. There are several strategies for reducing IL-1 activities (Table 1).

Rheumatoid arthritis

Several publications have reported that inflammatory autoimmune diseases developed spontaneously in IL-1Ra knockout mice. Horai et al. reported the development of an inflammatory erosive arthritis in IL-1Ra deficient mice. The arthropathy was marked by pannus invasion of the joint surface and histological evidence of marked synovial and periarticular inflammation, resembling to the changes typically seen in RA. No such disease developed in control mice, which had normal amounts of IL-1Ra.

The inflammasome

The recent identification of cytosol-expressed Nod-like receptors (NLR) has changed the concept of innate immunity as non-specific. NALP belonging to the NLR family have a N-terminal of pyrin domain (PYD). The PYD ensures interaction with the apoptosis-associated speck-like protein containing a caspase-recruitment-domain (ASC) adapter, which ensures the recruitment of an inflammatory caspase. NALP3 (Fig. 3) is probably the best understood of all, and is involved in the recognition of numerous

Conclusion

Anakinra (rIL-1Ra) is the anti-IL-1 molecule with wider efficacy and safety data, and is nowadays approved for therapeutical use, for RA and the AIS treatment. Other IL-1 inhibition strategies have been reported to be effective in vitro in RA, and are now on trials to establish their role on a clinical setting.

A new broad of therapeutical uses are now under investigation, namely the identification of IL-1β as a product of the inflammasome and NALP3 pathways, and its key-role in the so-called

Conflicts of interest

The authors have no conflicts of interest to declare.

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However, at high concentrations, IL-1β was observed to simultaneously induce IL-1R1 and IL-1R2, although IL-1R2 expression was found to be higher than that of IL-1R1. Whereas IL-1R1 mediates all the known biological activities of IL-1β (Farasat et al., 2008), IL-1R2, which lacks the TIR domain, functions as an endogenous inhibitor of IL-1β activity (Moltó and Olivé, 2010). Hence, when the concentration of IL-1β is low, up-regulation of IL-1R1 expression and down-regulation of IL-1R2 expression allows IL-1β to effectively exert its effects.
Interleukin-1β (IL-1β) is a pivotal proinflammatory cytokine that plays important roles in regulating immune responses and in inducing a series of inflammatory reactions in response to infection. Recently, increasing attention has focused on the regulatory mechanisms of IL-1β activity in teleosts. In this regard, IL-1 receptor type 1 plays a crucial role in immune responses, whereas IL-1 receptor type 2 is a decoy receptor that functions as an IL-1β signaling inhibitor. However, the interactions of these three proteins with respect to fish immunity have rarely been studied. In the present study, cDNAs of the il1b, il1r1, and il1r2 genes of the barbel steed (Hemibarbus labeo) were cloned and sequenced. Amino acid sequence analysis revealed that the IL-1β protein and its two receptors identified in barbel steed are conserved in most teleosts, whereas phylogenetic tree analysis indicated that these three proteins are closely related to those of cyprinids. In response to lipopolysaccharide treatment, expression of the genes encoding IL-1β and its two receptors was significantly upregulated in the immune-related tissues of barbel steed. Furthermore, expression of the il1r1 and il1r2 genes was induced in monocytes/macrophages in response to stimulation with recombinant IL-1β.
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Citation Excerpt :
In contrast, administration of IL-1Ra has resulted in marked improvements in experimental models of inflammatory arthritis and osteoarthritis (Jacques et al., 2006). Importantly, the recombinant IL-1Ra named anakinra has been approved for the treatment of patients with rheumatoid arthritis (Jesus and Goldbach-Mansky, 2014; Molto and Olive, 2010). Taken together, these findings highlight the key regulatory role and clinical implication of IL-1Ra in IL-1-related diseases.
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ReviewAnti-IL-1 molecules: New comers and new indications

Abstract

Introduction

Section snippets

Interleukin 1 family

Biological actions of IL-1

Biological actions of IL-1Ra

IL-1 Inhibition: new comers

Rheumatoid arthritis

The inflammasome

Conclusion

Conflicts of interest

Blood

Blood

Joint Bone Spine

Cytokine

Joint Bone Spine

Joint Bone Spine

Lancet

Joint Bone Spine

Joint Bone Spine

Joint Bone Spine

Joint Bone Spine

Lancet

Joint Bone Spine

Joint Bone Spine

The role of interleukin-1 in disease

N Engl J Med

Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases

Ann Rheum Dis

Mechanisms mediating the effects of cytokines on neuroendocrine functions in the rat

Ciba Found Symp

Interleukin-l and bone metabolism: a review

J Peridontol

Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis

Arthritis Rheum

Is there a rationale for combined TNF and IL-1 blocking in arthritis

Clin Exp Rheumatol

Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis

Lancet

Determination of cytokines in synovial fluids: correlation with diagnosis and histomorphological characteristics of synovial fluid

Ann Rheum Dis

Dysregulation of the in vivo production of interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Pathogenetic implications

Arthritis Rheum

Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy

J Immunol

Gene transfer to human joints: progress toward a gene therapy of arthritis

Proc Natl Acad Sci U S A

The human anti-Il-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis

Arthritis Res Ther

Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders

Curr Opin Mol Ther

Rilonacept in cryopyrin-associated periodic syndromes: the beginning of longer-acting interleukin-1 antagonism

Nat Clin Pract Rheumatol

Review
Anti-IL-1 molecules: New comers and new indications