IL-36␣ (IL-1F6), IL-36␤ (IL-1F8

No abstract

IntroductionThe interleukin-1 (IL-1) family of cytokines comprises 11 members, including IL-1␣, IL-1␤, IL-18, IL-33, and the recently renamed IL-36␣, ␤, ␥ (previously known as IL-1F6, IL-1F8, and IL-1F9). 1 All these cytokines use heterodimeric receptors for signaling. IL-1, IL-33, and IL-36 bind to specific receptor ␣-chains, which are IL-1RI for IL-1␣ and IL-1␤, T1/ST2 (also known as IL-33R) for IL-33, and IL-36R (previously termed IL-1Rrp2) for IL-36, and then recruit the same coreceptor IL-1R accessory protein (IL-1RAcP). IL-18 uses IL-18R␣ and the coreceptor IL-18R␤. On receptor binding, all IL-1 family cytokines activate similar intracellular signals, including NF-B and mitogenactivated protein kinase (MAPK) pathways. IL-1 receptor antagonist (IL-1Ra) and IL-36Ra (previously termed IL-1F5), 2 additional members of the IL-1 family, act as natural inhibitors for the biologic activities of IL-1 and IL-36, respectively. [2][3][4] IL-1␣, IL-1␤, IL-18, and IL-33 are produced by activated innate immune cells (neutrophils, monocytes, macrophages, and dendritic cells) and epithelial cells, and stimulate proinflammatory innate and adaptive immune responses. More specifically, these cytokines influence CD4 ϩ T-cell responses and their polarization into the different T helper (Th) subsets Th1, Th2, and Th17. IL-1 promotes the proliferation and survival of naive CD4 ϩ T cells and plays a critical role in Th17 differentiation. 5-9 IL-18 and IL-33 stimulate the polarization of CD4 ϩ T cells into Th1 and Th2, respectively,10 although the selectivity of these responses may be modulated by the cytokine environment. Consistently, Th1, Th2, and Th17 cells selectively express the IL-1 family cytokine receptors IL-18R␣, T1/ST2, and IL-1RI, respectively. 10 IL-36 cytokines and IL-36R are abundantly expressed by keratinocytes and other epithelial cell types. 4,[11][12][13] IL-36 plays a major role in mouse experimental skin inflammation and in human psoriasis both in the initiation and regulation of inflammatory responses. [14][15][16][17][18][19] Furthermore, the association of a form of generalized pustular psoriasis with genetic IL-36Ra deficiency in humans argues in favor of a significant role of IL-36 in inflammatory skin diseases. 20,21 Recently, we have shown that dendritic cells (DCs) express IL-36R and that IL-36 stimulates the production of several cytokines and enhances the expression of costimulatory molecules in bone marrow-derived DCs (BMDCs). The stimulatory effects of IL-36 were more robust than those of the other members of the IL-1 family. In addition, IL-36 stimulated the production of interferon ␥ (IFN-␥), IL-4, and to a lesser extent IL-17 by cultured splenocytes and activated CD4 ϩ T cells, and IL-36 was able to act as an adjuvant to stimulate Th1 responses in vivo. 22 In the results described herein we show that, among CD4 ϩ T-cell subsets, IL-36R is predominantly expressed by naive CD4 ϩ T (referred to also as naive Th) cells and that IL-36 stimulates activated naive CD4 ϩ T (referred to also as Th0) cell ...

Granzymes (gzms) are key components of T-killer (Tc) cells believed to mediate pro-apoptotic activities. Recent evidence suggests that gzms also possess non-cytotoxic activities that contribute to host defense. In this study, we show that Tc cells from lymphocytic choriomeningitis virus (LCMV)-infected wild-type (wt) and gzm A/B-deficient mice express similar levels of gzmK protein, with both mouse strains efficiently controlling infection. GzmK, in recombinant form or secreted by ex vivoderived LCMV-immune gzmAxB À/À Tc cells, lacks pro-apoptotic activity. Instead, gzmK induces primary mouse macrophages to process and secrete interleukin-1b, independent of the ATP receptor P2X 7 . Together with the finding that IL-1Ra (Anakinra) treatment inhibits virus elimination but not generation of cytotoxic Tc cells in wt mice, the data suggest that Tc cells control LCMV through non-cytotoxic processes that involve gzmK.