Interleukin-6 synthesis in human chondrocytes is regulated via the antagonistic actions of prostaglandin (PG)E2 and 15-deoxy-Δ(12,14)-PGJ2.

Elevated 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. 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-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. 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.

在类风湿关节炎（RA）患者的关节滑液中检测到白细胞介素 - 6（IL - 6）、前列腺素（PG）E2、PGD2及其脱水终产物15 - 脱氧 - Δ12,14 - PGJ2（15d - PGJ2）水平升高。PGE2直接刺激人关节软骨细胞中IL - 6的产生。然而，在有或无PGE2的情况下，PGD2和15d - PGJ2对人软骨细胞中IL - 6合成的影响尚未确定。据信，IL - 6的失调性过度产生是导致RA患者全身炎症表现和实验室检查异常的原因。 我们以T/C - 28a2软骨细胞系作为模型系统，报道外源性PGE2和PGD2/15d - PGJ2对人T/C - 28a2软骨细胞中IL - 6的合成具有拮抗作用。通过综合运用复杂的分子生物学技术，我们确定PGE2刺激Toll样受体4（TLR4）的合成，而TLR4反过来激活ERK1/2、PI3K/Akt和PKA/CREB通路，使NF - κB p65亚基磷酸化，从而导致NF - κB激活。激活的NF - κB p65亚基与IL - 6启动子结合，诱导人T/C - 28a2软骨细胞中IL - 6的合成。PGD2或15d - PGJ2同时下调TLR4并上调小窝蛋白 - 1，进而抑制PGE2依赖的ERK1/2、PI3 - K和PKA激活，并最终抑制软骨细胞中NF - κB依赖的IL - 6合成。 我们已经描绘了PGE2和PGD2/15d - PGJ2对人软骨细胞中IL - 6合成产生相反作用的信号级联。阐明软骨细胞中IL - 6合成和分泌的分子途径将为制定减轻RA患者炎症和疼痛的策略提供思路。