A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis

By Caroline E. Sutton, Corinna F. Brereton, B. Keogh, K. Mills, E. Lavelle. Journal of Experimental Medicine, 2006

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It was recently demonstrated that interleukin (IL)-23–driven IL-17–producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I–deficient (IL-1RI−/−) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI−/− compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI−/− mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI−/− mice, and IL-23–induced IL-17 production was substantially enhanced by IL-1α or IL-1β, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor κB, and novel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production. Tumor necrosis factor α also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.

Subfields: Immunology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/5c10b016603da70949b63d5a58fbc1172cb4a0c1

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Citations in the corpus

Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent (2010, background): “These mediators included IL6, IL12/23p40, the neutrophil chemokine KC (CXCL1), and, perhaps most strikingly, IL1, which was recently impli cated in BLMinduced fibrosis (Gasse et al., 2007) and in amplifying Th17 responses (Sutton et al., 2006, 2009; Fig.”
Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. (2009, methodology): “IL-17 protein production was assessed after 72 hr, but was detectable at low amounts after 48 hr (Sutton et al., 2006) and was maximal in the region of 10 ng/ml of IL-1b and IL-23 (data not shown), a concentration that was used for subsequent experiments.”
Fate mapping of interleukin 17-producing T cells in inflammatory responses (2011, background): “The expression of IL-1R1 on ex-T H 17 cells could be a useful marker for identifying cells that develop through a T H 17 program, as neither T H 1 nor T H 2 cells normally have substantial expression of this receptor, which has been shown to be crucial for the pathogenisis of autoimmune diseases suc”
TH-17 cells in the circle of immunity and autoimmunity (2007, background): “A likely candidate is IL-1, as IL-1R1-deficient mice fail to mount a robust T H -17 response after immunization, and IL-1R1-deficient T cells cultured with IL-23 do not produce IL-17 (ref”
Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells (2007, background): “For example, involvement of IL-1 in the generation of IL-17-producing cells has been documented in mouse models of arthritis, encephalomyelitis and vaccination against bacterial infection”
Th17 cells in human disease (2008, background): “The precise mechanisms are still unclear, but IL-23 may be involved in the TNF-a and IL-1b-induced secretion of IL-17 (13, 100).”
A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage (2007, background): “Sutton and colleagues showed that TNF synergized with IL-23 to enhance IL-17 and that this was IL-1 dependen”