Innate immunity is the first line of defense against infection, protecting the host during the development of adaptive immunity and critically affecting the nature of the adaptive response. We show that, in contrast to tumor necrosis factor alpha (TNF-alpha), the related protein TWEAK attenuates the transition from innate to adaptive mechanisms. TWEAK(-/-) mice had overabundant natural killer (NK) cells and displayed hypersensitivity to bacterial endotoxin, with their innate immune cells producing excess interferon (IFN)-gamma and interleukin (IL)-12. TWEAK inhibited stimulation of the transcriptional activator STAT-1 and induced p65 nuclear factor (NF)-kappa B association with histone deacetylase 1, repressing cytokine production. TWEAK(-/-) mice developed oversized spleens with expanded memory and T helper 1 (T(H)1) subtype cells upon aging and mounted stronger innate and adaptive T(H)1-based responses against tumor challenge. Thus, TWEAK suppresses production of IFN-gamma and IL-12, curtailing the innate response and its transition to adaptive T(H)1 immunity.
机构:
PO Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, AustraliaPO Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia
机构:
Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
Bonizzi, G
Karin, M
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Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
机构:Univ Calif San Francisco, Gladstone Inst Virol & Immunol, Dept Med, San Francisco, CA 94141 USA
Chen, LF
Greene, WC
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Univ Calif San Francisco, Gladstone Inst Virol & Immunol, Dept Med, San Francisco, CA 94141 USAUniv Calif San Francisco, Gladstone Inst Virol & Immunol, Dept Med, San Francisco, CA 94141 USA
机构:
PO Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, AustraliaPO Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia
机构:
Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
Bonizzi, G
Karin, M
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
机构:Univ Calif San Francisco, Gladstone Inst Virol & Immunol, Dept Med, San Francisco, CA 94141 USA
Chen, LF
Greene, WC
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Francisco, Gladstone Inst Virol & Immunol, Dept Med, San Francisco, CA 94141 USAUniv Calif San Francisco, Gladstone Inst Virol & Immunol, Dept Med, San Francisco, CA 94141 USA