Artículo de revista
Electrical stimulation induces IL-6 in skeletal muscle through extracellular ATP by activating Ca2 signals and an IL-6 autocrine loop
Fecha
2014Registro en:
Am J Physiol Endocrinol Metab 306: E869–E882, 2014.
Autor
Bustamante, Mario
Fernández Verdejo, Rodrigo
Jaimovich Pérez, Enrique
Buvinic Radic, Sonja
Institución
Resumen
S. Electrical stimulation induces IL-6 in skeletal muscle through
extracellular ATP by activating Ca2 signals and an IL-6 autocrine
loop. Am J Physiol Endocrinol Metab 306: E869 –E882, 2014. First
published February 11, 2014; doi:10.1152/ajpendo.00450.2013.—
Interleukin-6 (IL-6) is an important myokine that is highly expressed
in skeletal muscle cells upon exercise. We assessed IL-6 expression in
response to electrical stimulation (ES) or extracellular ATP as a
known mediator of the excitation-transcription mechanism in skeletal
muscle. We examined whether the canonical signaling cascade downstream
of IL-6 (IL-6/JAK2/STAT3) also responds to muscle cell
excitation, concluding that IL-6 influences its own expression through
a positive loop. Either ES or exogenous ATP (100 M) increased both
IL-6 expression and p-STAT3 levels in rat myotubes, a process
inhibited by 100 M suramin and 2 U/ml apyrase. ATP also evoked
IL-6 expression in both isolated skeletal fibers and extracts derived
from whole FDB muscles. ATP increased IL-6 release up to 10-fold.
STAT3 activation evoked by ATP was abolished by the JAK2
inhibitor HBC. Blockade of secreted IL-6 with a neutralizing antibody
or preincubation with the STAT3 inhibitor VIII reduced STAT3
activation evoked by extracellular ATP by 70%. Inhibitor VIII also
reduced by 70% IL-6 expression evoked by ATP, suggesting a
positive IL-6 loop. In addition, ATP increased up to 60% the protein
levels of SOCS3, a negative regulator of the IL-6 signaling pathway.
On the other hand, intracellular calcium chelation or blockade of
IP3-dependent calcium signals abolished STAT3 phosphorylation
evoked by either extracellular ATP or ES. These results suggest that
expression of IL-6 in stimulated skeletal muscle cells is mediated by
extracellular ATP and nucleotide receptors, involving IP3-dependent
calcium signals as an early step that triggers a positive IL-6 autocrine
loop.