Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 298, Issue 6, Pages C1445-C1456Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00508.2009
Keywords
arthritic disorders; protein expression; chondrocytes; signal transduction; arthritis
Categories
Funding
- National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [RO1 AR053358]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR053358] Funding Source: NIH RePORTER
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Wang P, Zhu F, Konstantopoulos K. Prostaglandin E2 induces interleukin-6 expression in human chondrocytes via cAMP/protein kinase A-and phosphatidylinositol 3-kinase-dependent NF-kappa B activation. Am J Physiol Cell Physiol 298: C1445-C1456, 2010. First published March 24, 2010; doi:10.1152/ajpcell.00508.2009.-Elevated levels of prostaglandin (PG) E2 and interleukin (IL)-6 have been reported in the cartilage and synovial fluid from patients with arthritic disorders. PGE(2) regulates IL-6 production in numerous different cells including macrophages and synovial fibroblasts. Although PGE2 stimulates IL-6 expression in human chondrocytes, the underlying signaling pathway of this process has yet to be delineated. Here, we investigate the mechanism of IL-6 induction in human T/C-28a2 chondrocytes treated with exogenously added PGE(2). PGE(2) induces IL-6 mRNA and protein expression via a cAMP-dependent pathway, reaching maximal levels after 60 min of stimulation before declining to baseline levels at 6 h. Forskolin, an adenylyl cyclase activator, also stimulates IL-6 expression in human chondrocytes in a dose- and time-dependent fashion. Inhibition of downstream effectors of cAMP activity such as protein kinase A (PKA) or phosphatidylinositol 3 kinase (PI3K) blocks PGE(2)- and forskolin-induced IL-6 upregulation. Simultaneous inhibition of PKA and PI3K reduces IL-6 expression in stimulated chondrocytes well below the basal levels of untreated cells. Gel shift, supershift, and chromatin immunoprecipitation assays reveal the activation and binding of the nuclear factor (NF)-kappa B p65 subunit to the IL-6 promoter, which is markedly suppressed by selective PI3K or PKA pharmacological inhibitors. p65 knockdown completely abrogates IL-6 mRNA synthesis in PGE(2)- and forskolin-primed chondrocytes. Cumulatively, our data show that PGE(2) and forskolin induce IL-6 expression in human chondrocytes via cAMP/PKA and PI3K-dependent pathways, which in turn regulate the activation and binding of p65 to the IL-6 promoter.
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