%0 Journal Article
%T ¦Â-Agonists Selectively Modulate Proinflammatory Gene Expression in Skeletal Muscle Cells via Non-Canonical Nuclear Crosstalk Mechanisms
%A Krzysztof Kolmus
%A Marleen Van Troys
%A Karlien Van Wesemael
%A Christophe Ampe
%A Guy Haegeman
%A Jan Tavernier
%A Sarah Gerlo
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0090649
%X The proinflammatory cytokine Tumour Necrosis Factor (TNF)-¦Á is implicated in a variety of skeletal muscle pathologies. Here, we have investigated how in vitro cotreatment of skeletal muscle C2C12 cells with ¦Â-agonists modulates the TNF-¦Á-induced inflammatory program. We observed that C2C12 myotubes express functional TNF receptor 1 (TNF-R1) and ¦Â2-adrenoreceptors (¦Â2-ARs). TNF-¦Á activated the canonical Nuclear Factor-¦ÊB (NF-¦ÊB) pathway and Mitogen-Activated Protein Kinases (MAPKs), culminating in potent induction of NF-¦ÊB-dependent proinflammatory genes. Cotreatment with the ¦Â-agonist isoproterenol potentiated the expression of inflammatory mediators, including Interleukin-6 (IL-6) and several chemokines. The enhanced production of chemotactic factors upon TNF-¦Á/isoproterenol cotreatment was also suggested by the results from migrational analysis. Whereas we could not explain our observations by cytoplasmic crosstalk, we found that TNF-R1-and ¦Â2-AR-induced signalling cascades cooperate in the nucleus. Using the IL-6 promoter as a model, we demonstrated that TNF-¦Á/isoproterenol cotreatment provoked phosphorylation of histone H3 at serine 10, concomitant with enhanced promoter accessibility and recruitment of the NF-¦ÊB p65 subunit, cAMP-response element-binding protein (CREB), CREB-binding protein (CBP) and RNA polymerase II. In summary, we show that ¦Â-agonists potentiate TNF-¦Á action, via nuclear crosstalk, that promotes chromatin relaxation at selected gene promoters. Our data warrant further study into the mode of action of ¦Â-agonists and urge for caution in their use as therapeutic agents for muscular disorders.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0090649