TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient mice.
TNF receptor-associated factor 1 (TRAF1) is a unique TRAF protein because it lacks a RING finger domain and is predominantly expressed in activated lymphocytes. To elucidate the function of TRAF1, we generated TRAF1-deficient mice. TRAF1(-/-) mice are viable and have normal lymphocyte development. TRAF1(-/-) T cells exhibit stronger than wild-type (WT) T cell proliferation to anti-CD3 mAb, which persisted in the presence of IL-2 or anti-CD28 antibodies. Activated TRAF1(-/-) T cells, but not TRAF1(+/+) T cells, responded to TNF by proliferation and activation of the NF-kappa B and AP-1 signaling pathways. This TNF effect was mediated by TNFR2 (p75) but not by TNFR1 (p55). Furthermore, skin from TRAF1(-/-) mice was hypersensitive to TNF-induced necrosis. These findings suggest that TRAF1 is a negative regulator of TNF signaling.
Tsitsikov
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EN
Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. tsitsikov_e@hub.tch.harvard.edu
Laouini
D
D
Dunn
I F
IF
Sannikova
T Y
TY
Davidson
L
L
Alt
F W
FW
Geha
R S
RS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D007136:Immunoglobulins / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D012871:Skin Diseases / Q000209:etiology / Q000473:pathology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007136:Immunoglobulins; D011506:Proteins; D018089:Superantigens; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha