Skeletal muscle interleukin-6 regulation in hyperthermia

Abstract

We previously reported that IL-6 production is acutely elevated in skeletal muscles exposed to ≥41°C, but the regulatory pathways are poorly understood. The present study characterizes the heat-induced transcriptional control of IL-6 in C2C12 muscle fibers. Hyperthermia exposure (42°C for 1 h) induced transcription from an IL-6 promoter-luciferase reporter plasmid. Heat shock factor-1 (HSF-1), a principal mediator of the heat shock response, was then tested for its role in IL-6 regulation. Overexpression of a constitutively active HSF-1 construct increased basal (37°C) promoter activity, whereas overexpression of a dominant negative HSF-1 reduced IL-6 promoter activity during basal and hyperthermia conditions. Since hyperthermia also induces stress-activated protein kinase (SAPK) signaling, we tested whether mutation of a transcription site downstream of SAPK, (i.e., activator protein-1, AP-1) influences IL-6 transcription in hyperthermia. The mutation had no effect on baseline reporter activity but completely inhibited heat-induced activity. We then tested whether pharmacologically induced states of protein stress, characteristic of cellular responses to hyperthermia and known to induce SAPKs and HSF-1, would induce IL-6 production in the absence of heat. The proteasome was inhibited with MG-132 in one set of experiments, and the unfolded protein response was stimulated with dithiothreitol, thapsigargin, tunicamycin, or castanospermine in other experiments. All treatments stimulated IL-6 protein secretion in the absence of hyperthermia. These studies demonstrate that IL-6 regulation in hyperthermia is directly controlled by HSF-1 and AP-1 signaling and that the IL-6 response in C2C12 myotubes is sensitive to categories of protein stress that reflect accumulation of damaged or unfolded proteins.

Increasing heat storage by wearing extra clothing during upper body exercise up-regulates heat shock protein 70 but does not modify the cytokine response

“…An acute cytokine response, similar to the one found following exercise, has also been reported following temperature increases in non-exercising conditions: this response has been found not only in isolated muscle ex vivo (Welc, Judge, & Clanton, 2013), but also when passively immersing humans in hot water (Laing et al, 2008;Leicht et al, 2015). Increased circulating cytokines in hot conditions may be a result of an increased secretion by immune cells that can be found in higher numbers in the circulation (Starkie, Hargreaves, Rolland, & Febbraio, 2005) and may change their secretory behaviour.…”

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

“…2010), and in muscle NF‐ κ B signaling did not appear to contribute to dysfunction in heat stroke models (Welc et al. 2012, 2013b). …”

“…In a heat stroke model, 1 h of hyperthermic exposure was sufficient to induce activation in SAPK signaling in skeletal muscle (Welc et al. 2013b) and AP‐1 protein abundance was increased by 15 (Diamond et al. 1999) and 30 min (Welc et al.…”

“…In several studies modeling heat stroke IL‐6 has been shown to be increased and cytoprotective (Leon 2007; Welc et al. 2012, 2013b; Phillips et al. 2015).…”

“…Moreover, heat stroke appears to induce inflammatory signaling via AP‐1 but not NF‐ κ B (Welc et al. 2013b), while more prolonged hyperthermic exposure activates both AP‐1 and NF‐ κ B (Ganesan et al. 2016).…”