IL-1RL2 and Its Ligands Contribute to the Cytokine Network in Psoriasis

Amgen, Seattle, WA 98119, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(7):4354-62. DOI: 10.4049/jimmunol.1000313
Source: PubMed


Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-α, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis.

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Available from: Muhammad Aslam
    • "The involvement of IL-23 in inflammatory/autoimmune disease is strongly supported by animal models demonstrating that IL-23-deficient mice (IL-23p19 −/− ) are resistant to experimentally induced autoimmune encephalitis and collagen-induced arthritis and that IL-23 neutralizing antibodies are efficacious in a number of inflammatory bowel disease and skin inflammation models (Cua et al., 2003; Murphy et al., 2003; van der Fits et al., 2009; Blumberg et al., 2010; Cox et al., 2012). Clinical trials with ustekinumab and briakinumab, which target the common p40 subunit shared by IL-12 and IL-23, in psoriasis and Crohn's disease, and tildrakizumab and guselkumab, which target the p19 subunit of IL-23, in psoriasis highlight the potential of IL-23 signalling blockade in human disease (Mannon et al., 2004; Kimball et al., 2012; Langley et al., 2012; Sandborn et al., 2012; Traczewski and Rudnicka, 2012; Reichert, 2013). "
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    ABSTRACT: Background and purpose: AMG 139 is a human anti-IL-23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. Experimental approach: The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys. Key results: AMG 139 bound with high affinity to both human and cynomolgus monkey IL-23 and specifically neutralized the biological activity of IL-23 without binding or blocking IL-12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half-life of 8.4-13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose-proportionally from 30 to 300 mg·kg(-1) and mean accumulation between the first and last dose ranged from 2- to 3.5-fold. Peripheral blood immunophenotyping, T-cell-dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg(-1) s.c. or i.v.). Conclusions and implications: The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.
    No preview · Article · Sep 2014 · British Journal of Pharmacology
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    • "According to the enhanced expression of IL-36R and IL-36α in inflamed joints we hypothesized that IL-36R signaling blockade could ameliorate disease onset as well as severity. Therefore, we used an antibody against the IL-36 receptor that has been shown to actively suppress the psoriasis phenotype in IL-36tg [5]. Using anti-IL-36R antibody or PBS, hTNFtg mice were treated from 4 to 8 weeks of age, beginning at a time point where the clinical onset is not detectable yet. "
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    ABSTRACT: Introduction Interleukin (IL)-36α is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. Recently, we could demonstrate that the receptor (IL-36R), its ligand IL-36α and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36α induces MAP-kinase and NFκB signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines. Methods To understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36α signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36α was tested in murine and human osteoclast assays. Results Diseased mice showed an increased expression of IL-36R and IL-36α in inflamed knee joints compared to wildtype controls. However, preventively treating mice with an IL-36R blocking antibody led to no changes in clinical onset and pattern of disease. Furthermore, blockade of IL-36 signaling did not change histological signs of TNF-induced arthritis. Additionally, no alteration on bone homeostasis was observed in ex vivo murine and human osteoclast differentiation assays. Conclusion Thus we conclude that IL-36α does not affect the development of inflammatory arthritis.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "The cross-talk between IL-36 ligands and Th17 mediators establishes a positive feedback loop involving keratinocytes, DCs, macrophages, and Th17 [60, 61]; as a consequence, activation of T cells is enhanced, recruitment of immune cells in psoriatic lesions is augmented, and the IL-23/Th17 axis is reinforced [55, 60]. In keeping, elevation of IL-36R ligands in psoriatic plaques is closely correlated with increased levels of TNF-alpha, IL-17, and IL-22, confirming the existence of a proinflammatory, self-reinforcing gene expression loop [56, 59]. "
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    ABSTRACT: Psoriasis vulgaris (PV) is a cutaneous inflammatory disorder stemming from abnormal, persistent activation of the interleukin- (IL-)23/Th17 axis. Pustular psoriasis (PP) is a clinicopathological variant of psoriasis, histopathologically defined by the predominance of intraepidermal collections of neutrophils. Although PP pathogenesis is thought to largely follow that of (PV), recent evidences point to a more central role for IL-1, IL-36, and IL-6 in the development of PP. We review the role of IL-6 in the pathogenesis of PV and PP, focusing on its cross-talk with cytokines of the IL-23/Th17 axis. Clinical inhibitors of IL-6 signaling, including tocilizumab, have shown significant effectiveness in the treatment of several inflammatory rheumatic diseases, including rheumatoid arthritis and juvenile idiopathic arthritis; accordingly, anti-IL-6 agents may potentially represent future promising therapies for the treatment of PP.
    Full-text · Article · Jul 2014 · Research Journal of Immunology
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