15-Deoxy-Δ(12,14)-prostaglandin J(2) modulates lipopolysaccharide-induced chemokine expression by blocking nuclear factor-κB activation via peroxisome proliferator activated receptor-γ-independent mechanism in renal tubular epithelial cells.

Inflammation is an unavoidable milieu for renal tubular cells during the development of renal tubulointerstitial fibrosis. It has been demonstrated that chemokines including monocyte chemoattractant protein-1 (MCP-1) and IL-8 are related to tubulointerstitial lesions. 15d-PGJ2 may modulate renal tubulointerstitial fibrosis progression via anti-inflammatory effects. However, no information is known about the effects of 15d-PGJ2 on chemokine expression in human proximal renal tubular cells (HPTECs) under inflammation. In the present study, HPTECs (HK-2 cells) were stimulated with lipopolysaccharide (LPS) only, or preincubated with 15d-PGJ2. IL-8 and MCP-1 expressions were determined by real-time PCR and ELISA. Nuclear factor-κB (NF-κB) location was detected by immunofluorescence analysis. The p-IKK, p-IκBα and p65/p50 were analyzed by immunoblotting. To investigate the mechanism of inhibitory effects of 15d-PGJ2, the PPAR-γ gene was effectively silenced in HK-2 cells using specific siRNA. The results showed that application of LPS significantly increased IL-8 and MCP-1 production. Phosphorylation of IκBα, IKK and nucleus translocation of NF-κB significantly increased in LPS-stimulated HK-2 cells. 15d-PGJ2 downregulated LPS-induced IL-8 and MCP-1 production. Interestingly, in PPAR-γ-deficient HK-2 cells, 15d-PGJ2 was still capable of inhibiting chemokines expression and attenuating phosphorylation of IκBα and nucleus translocation of NF-κB. Collectively, these results suggest that 15d-PGJ2 exerts anti-inflammatory actions on HK-2 cells by attenuating chemokines expression. 15d-PGJ2 inhibits chemokines expression via a PPAR-γ-independent way, which is related to block NF-κB pathway. Since NF-κB is an important regulator of the response of HPTECs to injury, PPAR-γ agonists may represent a key pharmacological target for ameliorating inflammation-associated tubulointerstitial fibrosis.

Lu Y ，Zhou Q ，Zhong F ，Guo S ，Hao X ，Li C ，Wang W ，Chen N ... -  《nephron experimental nephrology》

[PPAR-γ agonist inhibits the expressions of chemokines induced by IFN-γ and TNF-α in renal tubular epithelial cells].

Song Y ，Lin Q ，Zheng J ，Zhu X ，Yang S ... -  《-》

15-deoxy-Δ¹²,¹⁴-prostaglandin J₂ ameliorates endotoxin-induced acute lung injury in rats.

Liu D ，Geng Z ，Zhu W ，Wang H ，Chen Y ，Liang J ... -  《-》

A natural PPAR-gamma agonist, 15-deoxy-delta 12,14-prostaglandin J2, may act as an enhancer of PAI-1 in human proximal renal tubular cells under hypoxic and inflammatory conditions.

Kimura H ，Li X ，Torii K ，Okada T ，Takahashi N ，Fujii H ，Ishihara S ，Yoshida H ... -  《-》

15-deoxy-Δ(12,14) -prostaglandin-J2 and ciglitazone inhibit TNF-α-induced matrix metalloproteinase 13 production via the antagonism of NF-κB activation in human synovial fibroblasts.

Collagenase-3 (matrix metalloproteinase, MMP-13) plays an important role in the degradation of cartilage in pathologic conditions. MMP-13 is elevated in joint tissues in both rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, inflammation-stimulated synovial fibroblasts are able to release MMP-13 and other cytokines in these diseases. The peroxisome proliferator-activated receptor-γ (PPARγ) ligands are recently considered as new anti-inflammatory compounds and these ligands were reported to ameliorate inflammatory arthritis. The aim of this study is to evaluate the mechanisms how PPARγ ligands inhibit the inflammatory response in synovial fibroblasts. Two PPARγ ligands, cyclopentenone prostaglandin 15-deoxy-Δ(12,14) -prostaglandin-J2 (15d-PGJ2) and synthetic thiazolidinedione compound ciglitazone were examined in this study. Here we found that 15d-PGJ2 and ciglitazone markedly inhibited TNF-α-induced MMP-13 production in human synovial fibroblasts. In addition, activation of nuclear factor κB (NF-κB) is strongly associated with MMP-13 induction by TNF-α and the activation of NF-κB was determined by Western blot, reporter assay, and immunofluorescence. It was found that 15d-PGJ2 markedly attenuated the translocation of NF-κB by direct inhibition of the activation of IKK via a PPARγ-independent manner. Ciglitazone also inhibits TNF-α-induced MMP-13 expression by suppressing NF-κB activation mainly via the modulation of p38-MAPK. Collectively, our data demonstrate that 15d-PGJ2 and ciglitazone attenuated TNF-α-induced MMP-13 expression in synovial fibroblasts primarily through the modulation of NF-κB signaling pathways. These compounds may have therapeutic application in inflammatory arthritis.

Lin TH ，Tang CH ，Wu K ，Fong YC ，Yang RS ，Fu WM ... -  《-》