Background: Elevated levels of interleukin-6 (IL-6), prostaglandin (PG)E 2, PGD 2 and its dehydration end product 15-deoxy-Δ 12,14-PGJ 2 (15d-PGJ 2) have been detected in joint synovial fluids from patients with rheumatoid arthritis (RA). PGE 2 directly stimulates IL-6 production in human articular chondrocytes. However, the effects of PGD 2 and 15d-PGJ 2 in the absence or presence of PGE 2 on IL-6 synthesis in human chondrocytes have yet to be determined. It is believed that dysregulated overproduction of IL-6 is responsible for the systemic inflammatory manifestations and abnormal laboratory findings in RA patients. Methodology/Principal Findings: Using the T/C-28a2 chondrocyte cell line as a model system, we report that exogenous PGE 2 and PGD 2/15d-PGJ 2 exert antagonistic effects on IL-6 synthesis in human T/C-28a2 chondrocytes. Using a synthesis of sophisticated molecular biology techniques, we determined that PGE 2 stimulates Toll-like receptor 4 (TLR4) synthesis, which is in turn responsible for the activation of the ERK1/2, PI3K/Akt and PKA/CREB pathways that phosphorylate the NF-κB p65 subunit leading to NF-κB activation. Binding of the activated NF-κB p65 subunit to IL-6 promoter induces IL-6 synthesis in human T/C28a2 chondrocytes. PGD 2 or 15d-PGJ 2 concurrently downregulates TLR4 and upregulates caveolin-1, which in turn inhibit the PGE 2-dependent ERK1/2, PI3-K and PKA activation, and ultimately with NF-κB-dependent IL-6 synthesis in chondrocytes. Conclusions/Significance: We have delineated the signaling cascade by which PGE 2 and PGD 2/15d-PGJ 2 exert opposing effects on IL-6 synthesis in human chondrocytes. Elucidation of the molecular pathway of IL-6 synthesis and secretion by chondrocytes will provide insights for developing strategies to reduce inflammation and pain in RA patients.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)