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.