TRAF2 deficiency results in hyperactivity of certain TNFR1 signals and impairment of CD40-mediated responses.
Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) can interact with various members of the TNF receptor family. Previously, we reported that TRAF2-deficient mice die prematurely and have elevated serum TNF levels. In this study, we demonstrate that TRAF2-deficient macrophages produce increased amounts of nitric oxide (NO) and TNF in response to TNF stimulation. Furthermore, we could enhance the survival of TRAF2-deficient mice by eliminating either TNF or TNFR1. Using these double-knockout mice, we show that in the absence of TRAF2, the T helper-dependent antibody response, CD40-mediated proliferation, and NF-kappaB activation are defective. These data demonstrate two important roles of TRAF2, one as a negative regulator of certain TNFR1 signals and the other as a positive mediator of CD40 signaling.
Nguyen
L T
LT
Department of Immunology, University of Toronto, Ontario, Canada.
Duncan
G S
GS
Mirtsos
C
C
Ng
M
M
Speiser
D E
DE
Shahinian
A
A
Marino
M W
MW
Mak
T W
TW
Ohashi
P S
PS
Yeh
W C
WC
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D005260:Female; D017578:Immunoglobulin Class Switching; D007132:Immunoglobulin Isotypes; D018664:Interleukin-12 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014721:Vesicular stomatitis Indiana virus
D015703:Antigens, CD; D019013:CD40 Antigens; D007132:Immunoglobulin Isotypes; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse