Vigne S, Palmer G, Lamacchia C et al.IL-36R ligands are potent regulators of dendritic and T cells. Blood 118:5813-5823

Division of Rheumatology and Department of Pathology-Immunology, University of Geneva School of Medicine, Geneva, Switzerland.
Blood (Impact Factor: 10.45). 08/2011; 118(22):5813-23. DOI: 10.1182/blood-2011-05-356873
Source: PubMed


IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) are members of the IL-1 family of cytokines. These cytokines bind to IL-36R (IL-1Rrp2) and IL-1RAcP, activating similar intracellular signals as IL-1, whereas IL-36Ra (IL-1F5) acts as an IL-36R antagonist (IL-36Ra). In this study, we show that both murine bone marrow-derived dendritic cells (BMDCs) and CD4(+) T lymphocytes constitutively express IL-36R and respond to IL-36α, IL-36β, and IL-36γ. IL-36 induced the production of proinflammatory cytokines, including IL-12, IL-1β, IL-6, TNF-α, and IL-23 by BMDCs with a more potent stimulatory effect than that of other IL-1 cytokines. In addition, IL-36β enhanced the expression of CD80, CD86, and MHC class II by BMDCs. IL-36 also induced the production of IFN-γ, IL-4, and IL-17 by CD4(+) T cells and cultured splenocytes. These stimulatory effects were antagonized by IL-36Ra when used in 100- to 1000-fold molar excess. The immunization of mice with IL-36β significantly and specifically promoted Th1 responses. Our data thus indicate a critical role of IL-36R ligands in the interface between innate and adaptive immunity, leading to the stimulation of T helper responses.

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    • "On a cellular basis, IL-36R is also expressed on murine bone-marrow derived dendritic cells (BMDCs) and CD4+ T cells. Stimulation with its ligands induced the production of IL-12, IL-1β, IL-6, TNF-α and IL-23 in BMDCs, while stimulated CD4+ T cells produced IFN-γ, IL-4 and IL-17 [7]. "
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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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    • "Recently, a small number of publications have outlined some important roles played by other IL-1 family members (Mutamba et al. 2012; Ramadas et al. 2012; van de Veerdonk et al. 2012; Vigne et al. 2011; Vigne et al. 2012). Of note, the IL-36 agonists have the capacity to shape the adaptive immune response through their effects upon CD4 + T cells (Vigne et al. 2011). The presence of the IL-36 receptor (IL-1RL2) and IL-36RN genes in both the chicken and anole lizard genomes strongly implies that at least one IL-36 agonist gene must have Fig. 4 Schematic depicting the IL-33 locus in the human genome and a conserved syntenic region of the chicken genome. "
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    ABSTRACT: The interleukin-1 gene family encodes a group of related proteins that exhibit a remarkable pleiotropy in the context of health and disease. The set of indispensable functions they control suggests that these genes should be found in all eukaryotic species. The ligands and receptors of this family have been primarily characterised in man and mouse. The genomes of most non-mammalian animal species sequenced so far possess all of the IL-1 receptor genes found in mammals. Yet, strikingly, very few of the ligands are identifiable in non-mammalian genomes. Our recent identification of two further IL-1 ligands in the chicken warranted a critical reappraisal of the evolution of this vitally important cytokine family. This review presents substantial data gathered across multiple, divergent metazoan genomes to unambiguously trace the origin of these genes. With the hypothesis that all of these genes, both ligands and receptors, were formed in a single ancient ancestor, extensive database mining revealed sufficient evidence to confirm this. It therefore suggests that the emergence of mammals is unrelated to the expansion of the IL-1 family. A thorough review of this cytokine family in the chicken, the most extensively studied amongst non-mammalian species, is also presented. Electronic supplementary material The online version of this article (doi:10.1007/s00251-014-0780-7) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2014 · Immunogenetics
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    • "IL-36γ is a novel IL-1 family member cytokine that has been previously reported to be a potent recruiter and activator of naïve T cells that develop strong Type-1 functional polarity (78, 79). As in the case of LTβR ligands, IL-36 also triggers NFκB activation in IL-36R+ DC (79–82), which may prove pivotal for autocrine potentiation of Type-1 DC function and a pro-TLO TME. Whether tumor-associated VEC express IL-36R and activated NFκb in response to IL-36 remains an unanswered question. "
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    ABSTRACT: Ectopic lymphoid tissue, also known as tertiary lymphoid organs (TLO) develop adaptively within sites of chronic tissue inflammation, thereby allowing the host to efficiently crossprime specific immune effector cells within sites of disease. Recent evidence suggests that the presence of TLO in the tumor microenvironment (TME) predicts better overall survival. We will discuss the relevance of extranodal T cell priming within the TME as a means to effectively promote anti-tumor immunity and the strategic use of dendritic cell (DC)-based therapies to reinforce this clinically preferred process in the cancer-bearing host.
    Full-text · Article · Nov 2013 · Frontiers in Immunology
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