Abstract
In inflammatory cells, hyperthermia inhibits lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) gene expression and protein secretion. Since hyperthermia alone stimulates IL-6 in skeletal muscle, we hypothesized that it would amplify responses to other receptor-mediated stimuli. IL-6 regulation was tested in C2C12 myotubes and in soleus during treatment with epinephrine (EPI) or LPS. In EPI-treated myotubes (100 ng/ml), 1 h exposure at 40.5°C-42°C transiently increased IL-6 mRNA compared to EPI treatment alone at 37°C. In LPS-treated myotubes (1 μg/ml), exposure to 41°C-42°C also increased IL-6 mRNA. In isolated mouse soleus, similar amplifications of IL-6 gene expression were observed in 41°C, during both low (1 ng/ml) and high dose (100 ng/ml) EPI, but only in high dose LPS (1 μg/ml). In myotubes, heat increased IL-6 secretion during EPI exposure but had no effect or inhibited secretion with LPS. In soleus there were no effects of heat on IL-6 secretion during either EPI or LPS treatment. Mechanisms for the effects of heat on IL-6 mRNA were explored using a luciferase-reporter in C2C12 myotubes. Overexpression of heat shock factor-1 (HSF-1) had no impact on IL-6 promoter activity during EPI stimulation, but elevated IL-6 promoter activity during LPS stimulation. In contrast, when the activator protein-1 (AP-1) element was mutated, responses to both LPS and EPI were suppressed in heat. Using siRNA against activating transcription factor-3 (ATF-3), a heat-stress-induced inhibitor of IL-6, no ATF-3-dependent effects were observed. The results demonstrate that, unlike inflammatory cells, hyperthermia in muscle fibers amplifies IL-6 gene expression to EPI and LPS. The effect appears to reflect differential engagement of HSF-1 and AP-1 sensitive elements on the IL-6 gene, with no evidence for involvement of ATF-3. The functional significance of increased IL-6 mRNA expression during heat may serve to overcome the well-known suppression of protein synthetic pathways occurring during heat shock.
Highlights
Skeletal muscle produces IL-6 and other cytokines in response to receptor-mediated signals and from disturbances in internal homeostasis that result in cellular stress
In the heat alone group, IL-6 mRNA expression was consistently amplified as a function of temperature 41°C (Fig 1A), confirming our previous study [17]
Our results demonstrate that hyperthermia potentiates EPI- and LPS-induced IL-6 mRNA in both isolated myotubes and intact soleus when supraphysiologic doses of these mediators are used
Summary
Skeletal muscle produces IL-6 and other cytokines in response to receptor-mediated signals and from disturbances in internal homeostasis that result in cellular stress (reviewed in [1]). Receptor-mediated signal transduction occurs via abundant toll-like receptors (TLRs) [2,3], αand β-adrenergic receptors [4,5], ATP/adenosine receptors [3,6], and TNFα and IL-1β receptors [7] present on muscle fibers Ligands for these receptors are often present in the circulation in a variety of physiological and pathologic conditions, including disorders that can result in multiple organ dysfunction syndrome (MODS) [8], local muscle injury [9,10], heavy endurance exercise [11,12] and in sepsis [13,14]. These interactions may have additional importance in fever (core temperature: 38–41°C) or in heat illness (>40°C)
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