TIPE2, a Negative Regulator of Innate and Adaptive Immunity that Maintains Immune Homeostasis

Abstract

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 member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, designated TIPE2, that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid tissues, and its deletion in mice leads to multiorgan 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) activation. Importantly, TIPE2 binds to caspase-8 and inhibits activating protein-1 and nuclear factor-kappaB 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 function, and its selective expression in the immune system prevents hyperresponsiveness and maintains immune homeostasis.

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

“…30 Based on sequence homology, a TNFAIP8 family of proteins has very recently been defined consisting of TNFAIP8, TIPE1 (TNFAIP8Like1), TIPE2 and TIPE3. 31 The TNFAIP8 family members do not share significant sequence homology with other proteins apart from limited homology within the DED. However, a dramatic breakthrough in identifying their role has come with the generation of Tipe2 À/À mice.…”

“…However, a dramatic breakthrough in identifying their role has come with the generation of Tipe2 À/À mice. 31 The Tipe2 À/À mice exhibit inflammation in many organs, splenomegaly and premature death with defective innate and adaptive immune processes. TNFAIP8 may be the molecular link between glucocorticoidmediated cell death and immune homeostasis.…”

Expression of Tumor Necrosis Factor-alpha-induced Protein 8 in Pancreas Tissues and its Correlation with Epithelial Growth Factor Receptor Levels

“…Tumor necrosis factor-α-inducible protein 8 (TNFAIP8 or TIPE) family are very recently identified proteins and induced by TNF-α stimulation and by activation of transcription factor NF-κB (Patel et al, 1997;Kumar et al, 2000). TNFAIP8 family consists of TNFAIP8, TIPE1 (TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3), which share considerable sequence homology to regulate cell functions (Freundt et al, 2008;Sun et al, 2008). The early studies had showed that TNFAIP8 is an oncogenic factor that may play a role in tumor progression, and exogenous expression of TNFAIP8 enhances cell survival.…”

TIPE2 is negatively correlated with tissue factor and thrombospondin-1 expression in patients with bronchial asthma

“…However, silencing of TIPE2 expression may counteract the reduced inflammation and myocardial injury in NOD2-/-ischemic mice (27). Furthermore, down-regulation of TIPE2 expression may increase the expression of pro-inflammatory factors including IL-1, IL-10, IL-12 and tumor necrosis factor-α, which in turn induce liver inflammation and the progression of liver disease in TIPE2 -/-mice (16). In the present study, it was demonstrated that the expression of TIPE2 was reduced in the PBMCs of patients with asthma.…”

“…Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a gene that was initially identified in a mouse model of autoimmune encephalomyelitis (16). As a type of tumor necrosis factor-α-induced protein-8, TIPE2 is primarily expressed by the myeloid and lymphoid immune cells, particularly by T lymphocytes, mononuclear cells and macrophages (17,18).…”