The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease

Nature Immunology 8: 247-256 (2007)

Speaker：黃千晏                                                           Time：13:10~14:00, May 16, 2007

Commentator：徐麗君 老師                                        Place：Room 601

Abstract：

Autoimmune diseases arise from an aberrant immune response against substances and cells normally present in the body that leads to tissue damage. Cytokines dysregulation mediated by T helper cells is one mechanism of autoimmunity. Interleukin 17 (IL-17) produced by T_H-17 cells is an proinflammatory cytokine consisting of six members (IL-17A ─ IL-17F)¹. IL-17A and IL-17Fare the primary stimulators of IL-17-mediated inflammation and they require a receptor complex composed of IL-17RA and IL-17RC to trigger the signaling pathways that lead to the activation ofNFκB and consequently the production of proinflmmatory cytokines and chemokines. Both IL-17RA and IL-17RC contain a conserved cytoplasmic SEFIR (similar expression to fibroblast growth factor / IL-17R) domain. Previous studies have shown that Act1 (NFκB activator 1) also contains the SEFIR domain². The authors hypothesized that Act1 might be a mediator required for IL-17 signaling. First, they demonstrated that Act1 bound to IL-17R through SEFIR domain in HEK293 cells. They further showed that IL-17-mediated chemokines production was diminished in thelysate of Act1-deficient mouse embryonic fibroblasts (MEFs) and the serum of Act1-dificient mouse. They also found that other signaling molecules like TAK1 (TGF-β-avtivated kinase1) and TRAF6 (tumor necrosis factor receptor-associated factor) were recruited to the complex of Act1 and IL-17R. The authors then used two autoimmune mouse models of experimental autoimmuneencephamyelitis (EAE) and dextran sulfate sodium(DSS)-induced colitis to examine the effects of Act1 on IL-17-dependent autoimmune diseases. It was shown that Act1 induced IL-17-mediated autoimmune responses by upregulating chemokines to recruit neutrophils but not activating T helper cells, because the Act1-deficient mice still produced high level of interferon-γ(IFN-γ) and IL-17. Collectively, Act1 may be a key mediator of IL-17 signal transduction that recruites TAK1 and TRAF6 and initiates NF-κB pathway to result in inflammation and autoimmune responses.

References：

1. Kolls, J.K. and Linden, A. Interleukin-17 family members and inflammation. Immunity, 21: 467–476 (2004). 

2. Li, X. et al. Act1, an NF-B-activating protein. Proc. Natl. Acad. Sci. USA, 97: 10489–10493 (2000).