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TIPE2, a novel negative regulator of innate and adaptive immunity that maintains immune homeostasis
Author(s) -
Sun Honghong,
Gong Shunyou,
Carmody Ruaidhri,
Li Li,
Chen Youhai H.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.669.12
Subject(s) - immune system , homeostasis , acquired immune system , tumor necrosis factor alpha , inflammation , microbiology and biotechnology , immunity , innate immune system , biology , immunology , receptor , regulator , signal transduction , gene , biochemistry
Immune homeostasis is essential for the normal functioning of the immune system and its breakdown leads to fatal inflammatory diseases. We report here the identification of a novel member of the tumor necrosis factor‐induced protein‐8 family, designated TIPE2 that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid and inflamed tissues and its deletion in mice leads to multi‐organ inflammation, splenomegaly and premature death. TIPE2‐deficient animals are hypersensitive to septic shock, and TIPE2‐deficient cells are hyper‐responsive to Toll‐like receptor (TLR) and T cell receptor (TCR) signaling. Importantly, TIPE2 binds to caspase‐8, and inhibits activating protein‐1 and nuclear factor‐kB activation while promoting Fas‐induced apoptosis. Inhibiting caspase‐8 significantly blocks the hyper‐responsiveness of TIPE2‐deficient cells. These results establish that TIPE2 is an essential negative regulator of TLR and TCR signaling, and its selective expression in the immune system prevents hyper‐responsiveness and maintains immune homeostasis.