title: Toll-like receptor agonists and febrile range hyperthermia synergize to induce heat shock protein 70 expression and extracellular release.
abstract: Heat shock protein (Hsp) 70 expression can be stimulated by febrile range temperature (FRT). Hsp70 has been shown to be elevated in serum of patients with sepsis, and when released from cells, extracellular Hsp70 exerts endotoxin-like effects through Toll-like receptor 4 (TLR4) receptors. Circulating TLR agonists and fever both persist for the first several days of sepsis, and each can activate Hsp70 expression; however, the effect of combined exposure to FRT and TLR agonists on Hsp70 expression is unknown. We found that concurrent exposure to FRT (39.5 °C) and agonists for TLR4 (LPS), TLR2 (Pam3Cys), or TLR3 (poly(IC)) synergized to increase Hsp70 expression and extracellular release in RAW264.7 macrophages. The increase in Hsp70 expression was associated with activation of p38 and ERK MAP kinases, phosphorylation of histone H3, and increased recruitment of HSF1 to the Hsp70 promoter. Pretreatment with the p38 MAPK inhibitor SB283580 but not the ERK pathway inhibitor UO126 significantly reduced Hsp70 gene modification and Hsp70 expression in RAW cells co-exposed to LPS and FRT. In mice challenged with intratracheal LPS and then exposed to febrile range hyperthermia (core temperature, ∼39.5 °C), Hsp70 levels in lung tissue and in cell-free lung lavage were increased compared with mice exposed to either hyperthermia or LPS alone. We propose a model of how enhanced Hsp70 expression and extracellular release in patients concurrently exposed to fever and TLR agonists may contribute to the pathogenesis of sepsis.
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Gupta
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.forename: Mohan E
authors.initials: ME
authors.lastname: Tulapurkar
authors.forename: Ratnakar
authors.initials: R
authors.lastname: Potla
authors.forename: Tapan
authors.initials: T
authors.lastname: Maity
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.forename: Ishwar S
authors.initials: IS
authors.lastname: Singh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005334:Fever / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D012769:Shock / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors