Heat stroke activates a stress-induced cytokine response in skeletal muscle

J Appl Physiol (1985). 2013 Oct 15;115(8):1126-37. doi: 10.1152/japplphysiol.00636.2013. Epub 2013 Aug 8.


Heat stroke (HS) induces a rapid elevation in a number of circulating cytokines. This is often attributed to the stimulatory effects of endotoxin, released from damaged intestine, on immune cells. However, parenchymal cells also produce cytokines, and skeletal muscle, comprising a large proportion of body mass, is thought to participate. We tested the hypothesis that skeletal muscle exhibits a cytokine response to HS that parallels the systemic response in conscious mice heated to a core temperature of 42.4°C (TcMax). Diaphragm and hindlimb muscles showed a rapid rise in interleukin-6 (IL-6) and interleuin-10 (IL-10) mRNA and transient inhibition of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) throughout early recovery, a pattern that parallels changes in circulating cytokines. IL-6 protein was transiently elevated in both muscles at ∼32 min after reaching TcMax. Other responses observed included an upregulation of toll-like receptor-4 (TLR-4) and heat shock protein-72 (HSP-72) mRNA but no change in TLR-2 or HSP25 mRNA. Furthermore, c-jun and c-fos mRNA increased. Together, c-jun/c-fos form the activator protein-1 (AP-1) transcription factor, critical for stress-induced regulation of IL-6. Interestingly, a second "late-phase" (24 h) cytokine response, with increases in IL-6, IL-10, IL-1β, and TNF-α protein, were observed in hindlimb but not diaphragm muscle. These results demonstrate that skeletal muscle responds to HS with a distinct "stress-induced immune response," characterized by an early upregulation of IL-6, IL-10, and TLR-4 and suppression of IL-1β and TNF-α mRNA, a pattern discrete from classic innate immune cytokine responses.

Keywords: IL-10; IL-6; heat stress; myokines; toll-like receptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Gene Expression Regulation
  • Heat Stroke / genetics
  • Heat Stroke / immunology
  • Heat Stroke / metabolism*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Inflammation Mediators / metabolism*
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / immunology
  • Muscle, Skeletal / metabolism*
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Time Factors
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Cytokines
  • Heat-Shock Proteins
  • IL10 protein, mouse
  • Inflammation Mediators
  • Interleukin-1beta
  • Interleukin-6
  • RNA, Messenger
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interleukin-10