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Vigne, S. 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: 10.43). 08/2011; 118(22):5813-23. DOI: 10.1182/blood-2011-05-356873
Source: PubMed

ABSTRACT 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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    • "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.
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    • "The observed release of IL-36γ only by dying cells (Fig. 2–4) suggest that extracellular IL-36γ may also act as a danger signal to alert surrounding cells about the cell death. Combined with the reported involvement of IL-36γ in promoting inflammation (Blumberg et al., 2007; Debets et al., 2001; Ramadas et al., 2011; Towne et al., 2004) and activation of dendritic and T cells (Vigne et al., 2011) our observations support the notion of IL-36γ as an alarmin involved in activating the adaptive immune system in response to pathogen challenges such as viruses infecting the skin. "
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    ABSTRACT: IL-36 is the common name for the three IL-1 family members IL-36α, IL-36β, and IL-36γ, formerly known as IL-1F6, IL-1F8, and IL-1F9, respectively. IL-36 appears to have pro-inflammatory activities; however, the physiological function of these cytokines remains unknown. Expression of IL-36 by keratinocytes implies its possible involvement in innate immune responses in the skin. We observed that, of the three IL-36 isoforms, human keratinocytes express high levels of IL-36γ. IL-36γ mRNA expression was dramatically induced by the Toll-like receptor ligands polyinosinic-polycytidylic acid (poly(I:C)) and flagellin. Surprisingly, the IL-36γ protein was released by cells treated with poly(I:C), but remained intracellular in cells treated with flagellin only. poly(I:C), but not flagellin, induced cell death and caspase-3/7 activation. Inhibition of caspase-3/7 and caspase-1 blocked extracellular release of IL-36γ from poly(I:C)-treated cells. Furthermore, caspase-1 inhibition prevented poly(I:C)-induced caspase-3/7 activation. Interestingly, transcription of the gene IL36G was dependent on caspase-1, but not caspase-3/7, activation. This demonstrates that the pathways leading to IL36G transcription and caspase-3/7 activation branch after caspase-1. This divergence of the pathways allows the cells to enter a state of de novo protein synthesis before committing to pyroptosis. Overall, our observations suggest that IL-36γ may be an alarmin that signals the cause, e.g., viral infection, of cell death.
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