Hyperthermia differentially regulates TLR4 and TLR2-mediated innate immune response.
Fever influences multiple parameters of the immune response. However, the mechanisms by which fever manipulates immune response remain undefined. Here we present the evidences that fever range hyperthermia differentially regulates immune response to lipopolysaccharide (LPS) and lipoteichoic acids (LTA) through modulating Toll-like receptor (TLR) signaling. Pretreatment with 39.5 degrees C temperature enhanced LPS, but not LTA, induced NF-kappaB activation and TNF-alpha, IL-6 production in human macrophages. Consistently, expression of TLR4, but not TLR2, was up-regulated by 39.5 degrees C treatment. The increase in LPS-induced cytokine production was inhibited by TLR4-blocking antibody, indicating the enhancement of LPS-induced cytokine production by 39.5 degrees C pretreatment was TLR4-dependent. Pretreatment of mice with 39.5 degrees C temperature also enhanced LPS, but not LTA, induced TNF-alpha and IL-6 production in vivo. These results support the concept that fever range hyperthermia might activate innate immune response by promoting TLR4 expression and signaling, providing a possible mechanistic explanation for the function of fever in regulating innate immune responses.
Zhao
Wei
W
Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, PR China.
An
Huazhang
H
Zhou
Jun
J
Xu
Hongmei
H
Yu
Yizhi
Y
Cao
Xuetao
X
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D005260:Female; D005334:Fever / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013682:Teichoic Acids / Q000494:pharmacology; D013696:Temperature; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000906:Antibodies; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D020928:Mitogen-Activated Protein Kinases