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-diola
te (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
