Article

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

ABSTRACT

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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    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.
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