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?-agonists selectively modulate proinflammatory gene expression in skeletal muscle cells via non-canonical nuclear crosstalk mechanisms.


ABSTRACT: The proinflammatory cytokine Tumour Necrosis Factor (TNF)-? is implicated in a variety of skeletal muscle pathologies. Here, we have investigated how in vitro cotreatment of skeletal muscle C2C12 cells with ?-agonists modulates the TNF-?-induced inflammatory program. We observed that C2C12 myotubes express functional TNF receptor 1 (TNF-R1) and ?2-adrenoreceptors (?2-ARs). TNF-? activated the canonical Nuclear Factor-?B (NF-?B) pathway and Mitogen-Activated Protein Kinases (MAPKs), culminating in potent induction of NF-?B-dependent proinflammatory genes. Cotreatment with the ?-agonist isoproterenol potentiated the expression of inflammatory mediators, including Interleukin-6 (IL-6) and several chemokines. The enhanced production of chemotactic factors upon TNF-?/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 ?2-AR-induced signalling cascades cooperate in the nucleus. Using the IL-6 promoter as a model, we demonstrated that TNF-?/isoproterenol cotreatment provoked phosphorylation of histone H3 at serine 10, concomitant with enhanced promoter accessibility and recruitment of the NF-?B p65 subunit, cAMP-response element-binding protein (CREB), CREB-binding protein (CBP) and RNA polymerase II. In summary, we show that ?-agonists potentiate TNF-? action, via nuclear crosstalk, that promotes chromatin relaxation at selected gene promoters. Our data warrant further study into the mode of action of ?-agonists and urge for caution in their use as therapeutic agents for muscular disorders.

SUBMITTER: Kolmus K 

PROVIDER: S-EPMC3946252 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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β-agonists selectively modulate proinflammatory gene expression in skeletal muscle cells via non-canonical nuclear crosstalk mechanisms.

Kolmus Krzysztof K   Van Troys Marleen M   Van Wesemael Karlien K   Ampe Christophe C   Haegeman Guy G   Tavernier Jan J   Gerlo Sarah S  

PloS one 20140306 6


The proinflammatory cytokine Tumour Necrosis Factor (TNF)-α is implicated in a variety of skeletal muscle pathologies. Here, we have investigated how in vitro cotreatment of skeletal muscle C2C12 cells with β-agonists modulates the TNF-α-induced inflammatory program. We observed that C2C12 myotubes express functional TNF receptor 1 (TNF-R1) and β2-adrenoreceptors (β2-ARs). TNF-α activated the canonical Nuclear Factor-κB (NF-κB) pathway and Mitogen-Activated Protein Kinases (MAPKs), culminating i  ...[more]

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