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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    • "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.
    PLoS ONE 08/2014; 9(8):e101954. DOI:10.1371/journal.pone.0101954 · 3.23 Impact Factor
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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.
    Research Journal of Immunology 07/2014; 2014(85):964069. DOI:10.1155/2014/964069
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    • "Expression of several novel members of the IL-1 family (IL-1F6, IL-1F8, IL-1F9, and IL-1F5) was increased 2 to 3 orders of magnitude in psoriasis plaque versus uninvolved psoriatic skin, inducing the expression of antimicrobial peptides and matrix metalloproteinases in epidermal cells [27]. Chemical irritation of murine skin overexpressing the IL-1 family member IL-1F6 leads to an inflammatory condition similar to human psoriasis [28]. Clearly, from these studies, the significant role for members of the IL-1 family in psoriasis can be established. "
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    ABSTRACT: This study was carried out to examine the possible role of interleukin-1 (IL-1) in the functional insufficiency of regulatory T cells in psoriasis, by comparing the expression of IL-1 receptors on healthy control and psoriatic T cells. Patients with moderate-to-severe chronic plaque psoriasis and healthy volunteers, matched in age and sex, were selected for all experiments. CD4(+)CD25(-) effector and CD4(+)CD25(+)CD127(low) regulatory T cells were separated and used for the experiments. Expression of the mRNA of IL-1 receptors (IL-1R1, IL-1R2, and sIL-1R2) was determined by quantitative real-time RT-PCR. Cell surface IL-1 receptor expression was assessed by flow cytometry. Relative expression of the signal transmitting IL-1 receptor type 1 (IL-1R1) mRNA is higher in resting psoriatic effector and regulatory T cells, and activation induces higher IL-1R1 protein expression in psoriatic T cells than in healthy cells. Psoriatic regulatory and effector T cells express increased mRNA levels of the decoy IL-1 receptors (IL-1R2 and sIL-1R2) upon activation compared to healthy counterparts. Psoriatic T cells release slightly more sIL-1R2 into their surrounding than healthy T cells. In conclusion, changes in the expression of IL-1 receptors in psoriatic regulatory and effector T cells could contribute to the pathogenesis of psoriasis.
    Mediators of Inflammation 02/2014; 2014(3):472625. DOI:10.1155/2014/472625 · 3.24 Impact Factor
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