TWEAK attenuates the transition from innate to adaptive immunity.
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)-kappaB association with histone deacetylase 1, repressing cytokine production. TWEAK-/- mice developed oversized spleens with expanded memory and T helper 1 (TH1) subtype cells upon aging and mounted stronger innate and adaptive TH1-based responses against tumor challenge. Thus, TWEAK suppresses production of IFN-gamma and IL-12, curtailing the innate response and its transition to adaptive TH1 immunity.
Maecker
Heather
H
Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Varfolomeev
Eugene
E
Kischkel
Frank
F
Lawrence
David
D
LeBlanc
Heidi
H
Lee
Wyne
W
Hurst
Stephen
S
Danilenko
Dimitry
D
Li
Jun
J
Filvaroff
Ellen
E
Yang
Becky
B
Daniel
Dylan
D
Ashkenazi
Avi
A
D000818:Animals; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004731:Endotoxins / Q000276:immunology; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007111:Immunity, Cellular / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000033:anatomy & histology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000074050:TWEAK Receptor; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology*
D000074049:Cytokine TWEAK; D004731:Endotoxins; D018124:Receptors, Tumor Necrosis Factor; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D000074050:TWEAK Receptor; C491645:Tnfsf12 protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D018664:Interleukin-12; D007371:Interferon-gamma; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases