Interleukin-6 synthesis in human chondrocytes is regulated via the antagonistic actions of prostaglandin (PG)E 2 and 15-deoxy-δ 12,14-PGJ 2

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere27630
JournalPloS one
Volume6
Issue number11
DOIs
StatePublished - Nov 11 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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