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.
Subject(s)
Homeostasis , Immunity , Intracellular Signaling Peptides and Proteins/metabolism , Animals , Apoptosis , Caspase 8/metabolism , Cell Line , Encephalomyelitis, Autoimmune, Experimental , Humans , Immunity, Cellular , Inflammation/immunology , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/genetics , Lymphoid Tissue/immunology , Macrophages/immunology , Mice , Molecular Sequence Data , NF-kappa B/metabolism , Receptors, Antigen, T-Cell/immunology , Shock, Septic/immunology , Signal Transduction , Spinal Cord/immunology , T-Lymphocytes/immunology , Transcription Factor AP-1/metabolism , fas Receptor/metabolismABSTRACT
Both inflammatory diseases and cancer are associated with heightened protein translation. However, the mechanisms of translational regulation and the roles of translation factors in these diseases are not clear. Programmed cell death 4 (PDCD4) is a newly described inhibitor of protein translation. To determine the roles of PDCD4 in vivo, we generated PDCD4-deficient mice by gene targeting. We report here that mice deficient in PDCD4 develop spontaneous lymphomas and have a significantly reduced life span. Most tumors are of the B lymphoid origin with frequent metastasis to liver and kidney. However, PDCD4-deficient mice are resistant to inflammatory diseases such as autoimmune encephalomyelitis and diabetes. Mechanistic studies reveal that upon activation, PDCD4-deficient lymphocytes preferentially produce cytokines that promote oncogenesis but inhibit inflammation. These results establish that PDCD4 controls lymphoma genesis and autoimmune inflammation by selectively inhibiting protein translation in the immune system.
Subject(s)
Apoptosis Regulatory Proteins/immunology , Autoimmune Diseases/genetics , Inflammation/genetics , Lymphoma/genetics , RNA-Binding Proteins/immunology , Animals , Apoptosis Regulatory Proteins/deficiency , Autoimmune Diseases/immunology , Blotting, Western , Cell Line , Cytokines/biosynthesis , Enzyme-Linked Immunosorbent Assay , Immunohistochemistry , Inflammation/immunology , Lymphocytes/immunology , Lymphoma/immunology , Mice , Mice, Mutant Strains , Protein Array Analysis , Protein BiosynthesisABSTRACT
LIGHT is an important costimulatory molecule for T cell immunity. Recent studies have further implicated its role in innate immunity and inflammatory diseases, but its cellular and molecular mechanisms remain elusive. We report here that LIGHT is upregulated and functions as a proinflammatory cytokine in 2 independent experimental hepatitis models, induced by concanavalin A and Listeria monocytogenes. Molecular mutagenesis studies suggest that soluble LIGHT protein produced by cleavage from the cell membrane plays an important role in this effect through the interaction with the lymphotoxin-beta receptor (LTbetaR) but not herpes virus entry mediator. NK1.1+ T cells contribute to the production, but not the cleavage or effector functions, of soluble LIGHT. Importantly, treatment with a mAb that specifically interferes with the LIGHT-LTbetaR interaction protects mice from lethal hepatitis. Our studies thus identify a what we believe to be a novel function of soluble LIGHT in vivo and offer a potential target for therapeutic interventions in hepatic inflammatory diseases.
