TNF-alpha and glucocorticoid receptor interaction in L6 muscle cells: a cooperative downregulation of myosin heavy chain.
Sepsis is associated with increased expression of TNF-alpha with subsequent activation of nuclear factor-kappa B (NF-kappaB). The glucocorticoid receptor (GR) and NF-kappaB function as mutual antagonists and induction of the latter is believed to play a major role in the acquired glucocorticoid resistance that occurs in some septic patients. GR expression and function has been reported to be elevated in septic muscle suggesting a limited effect of the activated NF-kappaB on GR function in this context. In this study, the L6 myocyte cell line was used as an in vitro model for a sepsis-like condition in skeletal muscle. While short or long term treatment with TNF-alpha had no effect on GR expression, glucocorticoid-dependent downregulation of GR occurred with a kinetic profile that is accelerated relative to that observed in most cells. This downregulation was not affected by co-treatment or prior priming of L6 cells with TNF-alpha. The synthetic glucocorticoid, dexamethasone (DEX) blunted TNF-alpha-stimulated NF-kappaB activation in L6 cells. However, although effective at activating an NF-kappaB transcriptional response, TNF-alpha treatment exerted a minimal effect in myoblasts and no effect in myotubes on GR transcriptional activity. This limited impact of TNF-alpha on GR activity was not universal as TNF-alpha and DEX exerted an additive effect on the reduction in myosin heavy chain (MHC) protein expression caused by either agent alone. Thus, the selective perseverance of GR function in the presence of increased levels of glucocorticoids and TNF-alpha during sepsis or other inflammatory states may exacerbate muscle protein breakdown.
Dekelbab
Bassem H
BH
Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Witchel
Selma F
SF
DeFranco
Donald B
DB
D002460:Cell Line; D003907:Dexamethasone / Q000009:adverse effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D018995:Myosin Heavy Chains