title: Heat induces interleukin-6 in skeletal muscle cells via TRPV1/PKC/CREB pathways.
abstract: Interleukin-6 (IL-6) is released from skeletal muscle cells and induced by exercise, heat, catecholamine, glucose, lipopolysaccharide, reactive oxygen species, and inflammation. However, the mechanism that induces release of IL-6 from skeletal muscle cells remains unknown. Thermosensitive transient receptor potential (TRP) proteins such as TRPV1-4 play vital roles in cellular functions. In this study we hypothesized that TRPV1 senses heat, transmits a signal into the nucleus, and produces IL-6. The purpose of the present study is to investigate the underlying mechanisms whereby skeletal muscle cells sense and respond to heat. When mouse myoblast cells were exposed to 37-42°C for 2 h, mRNA expression of IL-6 increased in a temperature-dependent manner. Heat also increased IL-6 secretion in myoblast cells. A fura 2 fluorescence dual-wavelength excitation method showed that heat increased intracellular calcium flux in a temperature-dependent manner. Intracellular calcium flux and IL-6 mRNA expression were increased by the TRPV1 agonists capsaicin andN-arachidonoyldopamine and decreased by the TRPV1 antagonists AMG9810 and SB366791 and siRNA-mediated knockdown of TRPV1. TRPV2, 3, and 4 agonists did not change intracellular calcium flux. Western blotting with inhibitors demonstrated that heat increased phosphorylation levels of TRPV1, followed by PKC and cAMP response element-binding protein (CREB). PKC inhibitors, Gö6983 and staurosporine, CREB inhibitors, curcumin and naphthol AS-E, and knockdown of CREB suppressed the heat-induced increases in IL-6. These results indicate that heat increases IL-6 in skeletal muscle cells through the TRPV1, PKC, and CREB signal transduction pathway.NEW & NOTEWORTHYHeat increases the release of interleukin-6 (IL-6) from skeletal muscle cells. IL-6 has been shown to serve immune responses and metabolic functions in muscle. It can be anti-inflammatory as well as proinflammatory. However, the mechanism that induces release of IL-6 from skeletal muscle cells remains unknown. Here we show that heat increases IL-6 in skeletal muscle cells through the transient receptor potential vannilloid 1, PKC, and cAMP response element-binding protein signal transduction pathway.
authors.affiliation: Research Support Center, Dokkyo Medical University, Tochigi, Japan.|Department of Cardiovascular Medicine, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Syotaro
authors.initials: S
authors.lastname: Obi
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Tochigi, Japan; masamasa@pb4.so-net.ne.jp.|Heart Center, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Oguri
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Third Department of Internal Medicine, Teikyo University Chiba Medical Center, Chiba, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Nakamura
authors.affiliation: Department of Otolaryngology, University of Tokyo, Tokyo, Japan; and.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakuma
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Toyoda
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Tochigi, Japan.|Waon Therapy Research Institute, Tokyo, Japan.
authors.forename: Chuwa
authors.initials: C
authors.lastname: Tei
authors.affiliation: Research Support Center, Dokkyo Medical University, Tochigi, Japan.|Department of Cardiovascular Medicine, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Inoue
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology*; D018869:Heat-Shock Response / Q000276:immunology*; D006358:Hot Temperature; D015850:Interleukin-6 / Q000276:immunology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000276:immunology*; D011493:Protein Kinase C / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050916:TRPV Cation Channels / Q000276:immunology*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C577686:interleukin-6, mouse; D011493:Protein Kinase C
keywords: heat response transcription factor; heat sensor; hyperthermia