Abstract
BackgroundElevated levels of interleukin-6 (IL-6), prostaglandin (PG)E2, PGD2 and its dehydration end product 15-deoxy-Δ12,14-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.Methodology/Principal FindingsUsing 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-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. 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-κB-dependent IL-6 synthesis in chondrocytes.Conclusions/SignificanceWe 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.
Highlights
Rheumatoid arthritis (RA) is characterized by systemic and local inflammation, which results in cartilage and bone destruction
Caveolin-1 depletion increases IL-6 synthesis in both untreated control and PGD2 or 15d-PGJ2-treated T/C-28a2 cells (Fig. 2D and Fig. S2). These data illustrate that PGE2 and 15d-PGJ2 differentially regulate Toll-like receptor 4 (TLR4) and caveolin-1 expression, which in turn modulate IL-6 expression in human chondrocytes
The synovial fluid of rheumatoid arthritis (RA) patients relative to normal controls contains elevated levels of several soluble mediators including PGE2, PGD2/15d-PGJ2 and IL-6, which contribute to the systemic manifestations of the disease [9,17,27]
Summary
Rheumatoid arthritis (RA) is characterized by systemic and local inflammation, which results in cartilage and bone destruction. COX is known to exist in two isoforms: COX-1 and COX-2 Despite their similar active site structures, products and kinetics, only COX-2 is inducible and is primarily responsible for the elevated production of prostanoids in chondrocytes [2]. PGE2 and PGD2 are the major PGs synthesized by chondrocytes. PGD2 readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J2-series such as 15-deoxyD12,14-PGJ2 (15d-PGJ2). Elevated levels of interleukin-6 (IL-6), prostaglandin (PG)E2, PGD2 and its dehydration end product 15-deoxyD12,14-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. 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
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