Unique cytokine and chemokine responses to exertional heat stroke in mice

J Appl Physiol (1985). 2017 Feb 1;122(2):296-306. doi: 10.1152/japplphysiol.00667.2016. Epub 2016 Dec 1.


In heat stroke, cytokines are believed to play important roles in multiorgan dysfunction and recovery of damaged tissue. The time course of the cytokine response is well defined in passive heat stroke (PHS), but little is known about exertional heat stroke (EHS). In this study we used a recently developed mouse EHS model to measure the responses of circulating cytokines/chemokines and cytokine gene expression in muscle. A very rapid increase in circulating IL-6 was observed at maximum core temperature (Tc,max) that peaked at 0.5 h of recovery and disappeared by 3 h. IL-10 was not elevated at any time. This contrasts with PHS where both IL-6 and IL-10 peak at 3 h of recovery. Keratinocyte chemoattractant (KC), granulocyte-colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-2, MIP-1β, and monocyte chemoattractive factor-1 also demonstrated near peak responses at 0.5 h. Only G-CSF and KC remained elevated at 3 h. Muscle mRNA for innate immune cytokines (IL-6, IL-10, IL-1β, but not TNF-α) were greatly increased in diaphragm and soleus compared with similar measurements in PHS. We hypothesized that these altered cytokine responses in EHS may be due to a lower Tc,max achieved in EHS or a lower overall heat load. However, when these variables were controlled for, they could not account for the differences between EHS and PHS. We conclude that moderate exercise, superimposed on heat exposure, alters the pattern of circulating cytokine and chemokine production and muscle cytokine expression in EHS. This response may comprise an endocrine reflex to exercise in heat that initiates survival pathways and early onset tissue repair mechanisms.

New & noteworthy: Immune modulators called cytokines are released following extreme hyperthermia leading to heat stroke. It is not known whether exercise in hyperthermia, leading to EHS, influences this response. Using a mouse model of EHS, we discovered a rapid accumulation of interleukin-6 and other cytokines involved in immune cell trafficking. This response may comprise a protective mechanism for early induction of cell survival and tissue repair pathways needed for recovery from thermal injury.

Keywords: CXCL1; exercise; granulocyte-colony-stimulating factor; hyperthermia; interleukin-6.

MeSH terms

  • Animals
  • Chemokine CCL2 / metabolism
  • Chemokine CCL4 / metabolism
  • Chemokine CXCL2 / metabolism
  • Chemokines / metabolism*
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Gene Expression / physiology
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Heat Stroke / metabolism*
  • Heat Stroke / physiopathology*
  • Immunity, Innate / physiology
  • Interleukin-10 / metabolism
  • Interleukin-16 / metabolism
  • Interleukin-6 / metabolism
  • Keratinocytes / metabolism
  • Keratinocytes / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscles / metabolism
  • Muscles / physiopathology
  • Temperature
  • Tumor Necrosis Factor-alpha / metabolism


  • Chemokine CCL2
  • Chemokine CCL4
  • Chemokine CXCL2
  • Chemokines
  • Cytokines
  • Interleukin-16
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Granulocyte Colony-Stimulating Factor