title: Nitric oxide stimulates interleukin-6 production in skeletal myotubes.
abstract: Strenuous exercise leads to the up-regulation of interleukin-6 (IL-6) production and enhanced nitric oxide (NO) release within the contracting skeletal muscles. In this study, we investigated whether NO regulates IL-6 production in C2C12 myotubes. These cells exhibited a concentration-dependent increase in IL-6 production upon stimulation with NO donors (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate), (Z)-1-[N-(3-aminopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA-NONOate), and sodium nitroprusside (SNP). This treatment did not alter cGMP levels nor did the soluble guanylyl cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one(ODQ), alter this response. The NO-independent sGC activator 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY41-2272) and cyclic guanosine monophosphate (cGMP) analog 8Br-cGMP failed to induce IL-6 production. Upon exposure to NO donors, we observed an increase in Erk1/2 and p38 MAPK phosphorylation but not in SAPK/JNK. In addition, NO-induced IL-6 release was inhibited in a concentration-dependent fashion by the MEK1/2 inhibitor PD98059 and the p38 MAPK inhibitor SB203580 but not by the SAPK/JNK inhibitor SP600125. We conclude that NO-stimulated IL-6 production in differentiated C2C12 myotubes is cGMP-independent and mediated by activation of MAPK pathways.
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, Department of Critical Care and Pulmonary Services, Evangelismos Hospital, University of Athens Medical School , Athens, Greece.
authors.forename: Anastasia C
authors.initials: AC
authors.lastname: Makris
authors.forename: Yannis
authors.initials: Y
authors.lastname: Sotzios
authors.forename: Zongmin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Maria
authors.initials: M
authors.lastname: Makropoulou
authors.forename: Nektarios
authors.initials: N
authors.lastname: Papapetropoulos
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Zacharatos
authors.forename: Anastasia
authors.initials: A
authors.lastname: Pyriochou
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Theodoros
authors.initials: T
authors.lastname: Vassilakopoulos
mesh_terms: D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007114:Immunization; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
chemical_list: D006152:Cyclic GMP; D005419:Flavonoids; D007093:Imidazoles; D015850:Interleukin-6; D048052:Mitogen-Activated Protein Kinase 3; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011720:Pyrazoles; D011725:Pyridines; D011810:Quinoxalines; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one