Heat shock transcription factor 1 inhibits expression of IL-6 through activating transcription factor 3.
The febrile response is a complex physiological reaction to disease, including a cytokine-mediated increase in body temperature and the activation of inflammatory systems. Fever has beneficial roles in terms of disease prognosis, partly by suppressing the expression of inflammatory cytokines. However, the molecular mechanisms underlining the fever-mediated suppression of inflammatory gene expression have not been clarified. In this study, we showed that heat shock suppresses LPS-induced expression of IL-6, a major pyrogenic cytokine, in mouse embryonic fibroblasts and macrophages. Heat shock transcription factor 1 (HSF1) activated by heat shock induced the expression of activating transcription factor (ATF) 3, a negative regulator of IL-6, and ATF3 was necessary for heat-mediated suppression of IL-6, indicating a fever-mediated feedback loop consisting of HSF1 and ATF3. A comprehensive analysis of inflammatory gene expression revealed that heat pretreatment suppresses LPS-induced expression of most genes (86%), in part (67%) via ATF3. When HSF1-null and ATF3-null mice were injected with LPS, they expressed much higher levels of IL-6 than wild-type mice, resulting in an exaggerated febrile response. These results demonstrate a novel inhibitory pathway for inflammatory cytokines.
Takii
Ryosuke
R
Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube, Japan.
Inouye
Sachiye
S
Fujimoto
Mitsuaki
M
Nakamura
Tamami
T
Shinkawa
Toyohide
T
Prakasam
Ramachandran
R
Tan
Ke
K
Hayashida
Naoki
N
Ichikawa
Hitoshi
H
Hai
Tsonwin
T
Nakai
Akira
A
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D025461:Feedback, Physiological; D005334:Fever; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D012097:Repressor Proteins; D014157:Transcription Factors / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
D051700:Activating Transcription Factor 3; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D015850:Interleukin-6; D012097:Repressor Proteins; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C490017:Hsf1 protein, mouse