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

Welc, Steven S.; Clanton, Thomas L.; Dineen, Shauna M.; Leon, Lisa R.

doi:10.1152/japplphysiol.00636.2013

Cited by 66 publications

(70 citation statements)

References 73 publications

(111 reference statements)

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“…1999; Welc et al. 2013a). In a heat stroke model, 1 h of hyperthermic exposure was sufficient to induce activation in SAPK signaling in skeletal muscle (Welc et al.…”

Section: Discussionmentioning

confidence: 99%

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Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

et al. 2017

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Despite well‐studied clinical manifestations, intracellular mechanisms of prolonged hyperthermic injury remain unclear, especially in skeletal muscle. Given muscle's large potential to impact systemic inflammation and metabolism, the response of muscle cells to heat‐mediated injury warrants further investigation. We have previously reported increased activation of NF‐κB signaling and increased NF‐κB and AP‐1‐driven transcripts in oxidative skeletal muscle following 12 h of heat stress. The purpose of this investigation was to examine early heat stress‐induced inflammatory signaling in skeletal muscle. We hypothesized that heat stress would increase NF‐κB and AP‐1 signaling in oxidative skeletal muscle. To address this hypothesis, 32 gilts were randomly assigned to one of four treatment groups (n = 8/group): control (0 h: 21°C) or exposed to heat stress conditions (37°C) for 2 h (n = 8), 4 h (n = 8), or 6 h (n = 8). Immediately following environmental exposure pigs were euthanized and the red portion of the semitendinosus muscle (STR) was harvested. We found evidence of NF‐κB pathway activation as indicated by increased protein abundance of NF‐κB activator IKK‐α following 4 h and increased total NF‐κB protein abundance following 6 h of heat stress. Heat stress also stimulated AP‐1 signaling as AP‐1 protein abundance was increased in nuclear fractions following 4 h of heat stress. Interleukin‐6 protein abundance and activation of the JAK/STAT pathway were decreased in heat stressed muscle. These data indicate that heat stress activated inflammatory signaling in the porcine STR muscle via the AP‐1 pathway and early activation of the NF‐κB pathway.

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“…1999; Welc et al. 2013a). In a heat stroke model, 1 h of hyperthermic exposure was sufficient to induce activation in SAPK signaling in skeletal muscle (Welc et al.…”

Section: Discussionmentioning

confidence: 99%

“…1999) and 30 min (Welc et al. 2013a) of hyperthermia. In our current study, we found evidence supporting activated AP‐1 signaling as relative protein abundance of AP‐1 was increased in nuclear fractions following 4 and 6 h of heat stress compared to thermoneutral.…”

Section: Discussionmentioning

confidence: 99%

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

et al. 2017

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“…; Welc et al . ). IL‐6 has been found to have many different functions that fall under categories of both pro‐ and anti‐inflammatory activity, wound healing, cell survival signalling and metabolic control, and has been shown to have a number of functional roles in acute and chronic illnesses.…”

Section: Introductionmentioning

confidence: 97%

Protection of intestinal injury during heat stroke in mice by interleukin‐6 pretreatment

Phillips

Welc

Wallet

et al. 2015

The Journal of Physiology

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Key pointsr Heat stroke afflicts thousands of humans each year, worldwide. r The immune system responds to hyperthermia exposure resulting in heat stroke by producing an array of immunological proteins, such as interleukin-6 (IL-6). However, the physiological functions of IL-6 and other cytokines in hyperthermia are poorly understood.r We hypothesized that IL-6 plays a protective role in conditions of heat stroke. To test this, we gave small IL-6 supplements to mice prior to exposing them to hot environments sufficient to induce conditions of heat stroke.r Pretreatment with IL-6 resulted in improved ability to withstand heat exposure in anaesthetized mice, it protected the intestine from injury, reducing the permeability of the intestinal barrier, and it attenuated the release of other cytokines involved in inflammation.r The results support the hypothesis that IL-6 is a 'physiological stress hormone' that plays an important role in survival during acute life-threatening conditions such as heat stroke.Abstract The role of interleukin-6 (IL-6) in hyperthermia and heat stroke is poorly understood. Plasma IL-6 is elevated following hyperthermia in animals and humans, and IL-6 knockout mice are more intolerant of severe hyperthermia. We evaluated the effect of IL-6 supplementation on organ injury following severe hyperthermia exposure in anaesthetized mice. Two hours prior to hyperthermia, mice were treated with 0.6 μg intraperitoneal IL-6, or identical volumes of saline in controls. Mice were anaesthetized, gavaged with FITC-dextran for measures of gastrointestinal permeability, and exposed to incremental (0.5°C every 30 min) increases in temperature. Heating stopped when maximum core temperature (T c ) of 42.4°C was attained (T c,max ). The mice recovered at room temperature (22°C) for 30 or 120 min, at which time plasma and tissues were collected. IL-6-treated mice, on average, required 25 min longer to attain T c,max . Injury and swelling of the villi in the duodenum was present in untreated mice after 30 min of recovery. These changes were blocked by IL-6 treatment. IL-6 also reduced gastrointestinal permeability, assayed by the accumulation of FITC-dextran in plasma. Plasma cytokines were also attenuated in IL-6-treated animals, including significant reductions in TNFα, MCP-1 (CXCL2), RANTES (CCL5) and KC (CCL5). The results demonstrate that IL-6 has a protective influence on the pattern of physiological responses to severe hyperthermia, suggesting that early endogenous expression of IL-6 may provide a protection from the development of organ damage and inflammation.

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“…Plasma TNF␣ was undetectable at the end of heat exposure in both vehicle-and infliximab-treated rats, and the antibody had no effect on maximum T c (T c,Max ϭ 43.0°C) or other heat stroke responses. We showed in mice that plasma TNF␣ was either unchanged or decreased at T c,Max and later time points of heat stroke recovery (7,15,30), yet robust increases in sTNFRI and II were observed throughout recovery (2). Plasma sTNFRs have been shown to protect against TNF␣-induced cytokine production and cytotoxicity (29), which is congruent with the purported protective actions of the soluble receptors in heat stroke patients (10).…”

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confidence: 99%

Attenuated thermoregulatory, metabolic, and liver acute phase protein response to heat stroke in TNF receptor knockout mice

Leon

Dineen

Bláha

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Tumor necrosis factor (TNF) is considered an adverse mediator of heat stroke (HS) based on clinical studies showing high serum levels. However, soluble TNF receptors (sTNFR; TNF antagonists) were higher in survivors than nonsurvivors, and TNFR knockout (KO) mice showed a trend toward increased mortality, suggesting TNF has protective actions for recovery. We delineated TNF actions in HS by comparing thermoregulatory, metabolic, and inflammatory responses between B6129F2 (wild type, WT) and TNFR KO mice. Before heat exposure, TNFR KO mice showed ~0.4°C lower core temperature (T(c); radiotelemetry), ~10% lower metabolic rate (M(r); indirect calorimetry), and reduced plasma interleukin (IL)-1α and sIL-1RI than WT mice. KO mice selected warmer temperatures than WT mice in a gradient but remained hypothermic. In the calorimeter, both genotypes showed a similar heating rate, but TNFR KO maintained lower T(c) and M(r) than WT mice for a given heat exposure duration and required ~30 min longer to reach maximum T(c) (42.4°C). Plasma IL-6 increased at ~3 h of recovery in both genotypes, but KO mice showed a more robust sIL-6R response. Higher sIL-6R in the KO mice was associated with delayed liver p-STAT3 protein expression and attenuated serum amyloid A3 (SAA3) gene expression, suggesting the acute phase response (APR) was attenuated in these mice. Our data suggest that the absence of TNF signaling induced a regulated hypothermic state in the KO mice, TNF-IL-1 interactions may modulate T(c) and M(r) during homeostatic conditions, and TNF modulates the APR during HS recovery through interactions with the liver IL-6-STAT3 pathway of SAA3 regulation.

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

Cited by 66 publications

References 73 publications

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

Protection of intestinal injury during heat stroke in mice by interleukin‐6 pretreatment

Attenuated thermoregulatory, metabolic, and liver acute phase protein response to heat stroke in TNF receptor knockout mice

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