Tsubouchi Y, Kawahito Y, Kohno M, Inoue K, Hla T, Sano H
First Department of Internal Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
Biochem Biophys Res Commun. 2001 May 18;283(4):750-5. doi: 10.1006/bbrc.2001.4847.
Rheumatoid arthritis (RA) is a chronic polyarticular joint disease associated with massive synovial proliferation, inflammation, and angiogenesis. PPAR-gamma ligands, both 15-deoxy-Delta(12,14)-prostaglandin J2 (15d- PGJ2) and troglitazone (TRO), can inhibit the growth of RA synoviocytes in vitro, and suppress the chronic inflammation of adjuvant-induced arthritis in rats, but the potency of 15d-PGJ2 is higher than TRO. Prostaglandin (PG) E2 plays important roles in joint erosion and synovial inflammation. In the present study, 15d-PGJ2, but not TRO and other prostanoids, suppressed interleukin (IL)-1beta-induced PGE2 synthesis in rheumatoid synovial fibroblasts (RSFs) through the inhibition of cyclooxygenase (COX-2) and cytosolic phospholipase A2 (cPLA2) expression. Furthermore, the inhibition was not affected by pretreatment with anti-PPAR-gamma antibody. It means that this anti-inflammatory effect of 15d-PGJ2 for PG synthesis may be independent of PPAR-gamma and 15d-PGJ2 is a key regulator of negative feedback of the arachidonate cascade on the COX pathway. These findings provide new insight into the feedback mechanism of the arachidonate cascade.
类风湿关节炎（RA）是一种慢性多关节疾病，与大量滑膜增生、炎症和血管生成相关。过氧化物酶体增殖物激活受体γ（PPAR-γ）配体，即15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）和曲格列酮（TRO），在体外可抑制RA滑膜细胞的生长，并抑制大鼠佐剂性关节炎的慢性炎症，但15d-PGJ2的效力高于TRO。前列腺素（PG）E2在关节侵蚀和滑膜炎症中起重要作用。在本研究中，15d-PGJ2而非TRO和其他前列腺素通过抑制环氧化酶（COX-2）和胞质磷脂酶A2（cPLA2）的表达，抑制白细胞介素（IL）-1β诱导的类风湿滑膜成纤维细胞（RSF）中PGE2的合成。此外，该抑制作用不受抗PPAR-γ抗体预处理的影响。这意味着15d-PGJ2对PG合成的这种抗炎作用可能独立于PPAR-γ，且15d-PGJ2是花生四烯酸级联反应对COX途径负反馈的关键调节因子。这些发现为花生四烯酸级联反应的反馈机制提供了新的见解。
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