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Research Article

FEBRILE RANGE TEMPERATURE MODIFIES CYTOKINE GENE EXPRESSION IN LPS-STIMULATED MACROPHAGES BY DIFFERENTIALLY MODIFYING NF-KB RECRUITMENT TO CYTOKINE PROMOTERS

¹University of Maryland School of Medicine ²University of Utah

Submitted 30 July 2009 ; revised 5 October 2009 ; accepted in final form 9 October 2009

We have previously shown that exposure to febrile-range temperatures (FRT, 39.5-40°C) reduces LPS-induced TNF expression, in part through the direct interaction of heat shock factor-1 (HSF1) with the TNF gene promoter. However, it is not known whether exposure to FRT also modifies more proximal LPS-induced signaling events. Using HSF1-null mice, we confirmed that HSF1 is required for FRT-induced repression of TNF in vitro by LPS-stimulated bone marrow derived macrophages and in vivo in mice challenged intratracheally with LPS. Exposing LPS-stimulated RAW 264.7 mouse macrophages to FRT reduced TNF expression while increasing IL-1β expression despite the two genes sharing a common MyD88-dependent pathway. Global activation of the three LPS-induced signaling intermediates that lead to cytokine gene expression, ERK and p38 MAPKs and NF-B, was not affected by exposing RAW 264.7 cells to FRT as assessed by ERK and p38 phosphorylation and NF-B in vitro DNA-binding activity and activation of a NF-B-dependent synthetic promoter. However, chromatin immunoprecipitation (ChIP) analysis demonstrated that exposure to FRT reduced LPS-induced recruitment of NF-B p65 to the TNF promoter while simultaneously increasing its recruitment to the IL-1β promoter. These data suggest that FRT exerts its effects on cytokine gene expression in a gene specific manner through distal effects on promoter activation rather than proximal receptor activation and signal transduction.

hyperthermia; fever; HSF1; heat shock