c-Fos suppresses systemic inflammatory response to endotoxin.
We explored the role of the transcription factor c-Fos in lipopolysaccharide (LPS)-induced cytokine response using mice lacking c-Fos (Fos-/- mice). Compared with wild-type controls, Fos-/- macrophages and mice showed significantly enhanced production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12 p40, but reduced production of the anti-inflammatory cytokine IL-10. Bandshift analysis revealed that LPS-induced NF-kappaB binding activity to a functional site in the TNF-alpha promoter was significantly higher in Fos-/- than in wild-type macrophages. Using telemetry, we monitored body temperature and heart rate after LPS injection and found that Fos-/- mice undergo more severe hypothermia and bradycardia than wild-type mice. Such shock responses in Fos-/- mice were significantly reversed by neutralizing TNF-alpha. These data reveal a novel in vivo role for c-Fos as an anti-inflammatory transcription factor acting through suppression of NF-kappaB activity.
Ray
Neelanjan
N
Department of Microbiology and Immunology, School of Medicine, Keio University, 35 Shinanomachi, 160-8582 Tokyo, Japan.
Kuwahara
Masayoshi
M
Takada
Yasunari
Y
Maruyama
Kenta
K
Kawaguchi
Tomohiro
T
Tsubone
Hirokazu
H
Ishikawa
Hiromichi
H
Matsuo
Koichi
K
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D024202:Electrophoretic Mobility Shift Assay; D008070:Lipopolysaccharides / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012772:Shock, Septic / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha