by Pu Wang, Fei Zhu, Konstantinos Konstantopoulos

Elevated levels of interleukin-6 (IL-6), prostaglandin (PG)E₂, PGD₂ and its dehydration end product 15-deoxy-?^12,14-PGJ₂ (15d-PGJ₂) have been detected in joint synovial fluids from patients with rheumatoid arthritis (RA). PGE₂ directly stimulates IL-6 production in human articular chondrocytes. However, the effects of PGD₂ and 15d-PGJ₂ in the absence or presence of PGE₂ 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.

Using the T/C-28a2 chondrocyte cell line as a model system, we report that exogenous PGE₂ and PGD₂/15d-PGJ₂ exert antagonistic effects on IL-6 synthesis in human T/C-28a2 chondrocytes. Using a synthesis of sophisticated molecular biology techniques, we determined that PGE₂ 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-?B p65 subunit leading to NF-?B activation. Binding of the activated NF-?B p65 subunit to IL-6 promoter induces IL-6 synthesis in human T/C28a2 chondrocytes. PGD₂ or 15d-PGJ₂ concurrently downregulates TLR4 and upregulates caveolin-1, which in turn inhibit the PGE₂-dependent ERK1/2, PI3-K and PKA activation, and ultimately with NF-?B-dependent IL-6 synthesis in chondrocytes.

We have delineated the signaling cascade by which PGE₂ and PGD₂/15d-PGJ₂ 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.