Association between urokinase gene 3'-UTR T/C polymorphism and Chinese patients with rheumatoid arthritis in Taiwan

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Title:	Association between urokinase gene 3'-UTR T/C polymorphism and Chinese patients with rheumatoid arthritis in Taiwan
Authors:	Huang, CM;Chen, CL;Tsai, JJP;Tsai, CH;Tsai, FJ
Contributors:	附設醫院內科部風濕免疫科;Taichung Healthcare & Management Univ, Dept Med Genet, Grad Inst Bioinformat, China Med Univ Hosp,Dept Internal Med,Div Immunol, Taichung, Taiwan;Foo Yin Inst Technol, Kaohsiung, Taiwan
Date:	2004
Issue Date:	2010-09-24 14:20:44 (UTC+8)
Publisher:	CLINICAL & EXPER RHEUMATOLOGY
Abstract:	1 The present study was undertaken to investigate the anti-inflammatory effects of a synthetic compound, LCY-2-CHO, on the expression of inducible nitric oxide synthase (iNOS), COX-2, and TNF-alpha in murine RAW264.7 macrophages. 2 Within 1-30 muM, LCY-2-CHO concentration-dependently inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E-2 (PGE(2)), and tumor necrosis factor-alpha (TNF-alpha) formation, with IC50 values of 2.3, 1, and 0.8 muM, respectively. Accompanying inhibition of LPS-induced iNOS, cyclooxygenase-2 (COX-2), and pro-TNF-alpha proteins was observed. 3 Reverse transcription-polymerase chain reaction (RT-PCR) and promoter analyses indicated that iNOS expression was inhibited at the transcriptional level (IC50 = 2.3 muM), that inhibition of COX-2 expression only partially depended on gene transcription (IC50 = 7.6 muM), and that TNF-alpha transcription was unaffected. 4 Transcriptional assays revealed that activation of AP-1, but not NF-kappaB, was concomitantly blocked by LCY-2-CHO. Our results showed that LCY-2-CHO was capable of interfering with post-transcriptional regulation, altering the stability of COX-2and TNF-alpha mRNAs. 5 Since the 3'-untranslated region (3' UTR) of both COX-2 and TNF-alpha mRNA contains a p38 mitogen-activated protein kinase (MAPK)-regulated element involved in mRNA stability, we assessed the effect of LCY-2-CHO on p38 MAPK. Our data clearly indicated an inhibition (IC50 = 1.7 muM) of LPS-mediated p38 MAPK activity, but not of extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) activity. However, kinase assays ruled out a direct inhibition of p38 MAPK action. The selective p38 MAPK inhibitor, SB203580, inhibited the promoter activities of iNOS and COX-2 rather than that of TNF-alpha. 6 In conclusion, LCY-2-CHO downregulates inflammatory iNOS, COX-2, and TNF-alpha gene expression in macrophages through interfering with p38 MAPK and AP-1 activation.
Relation:	CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 22(2):219-222
Appears in Collections:	[China Medical University Hospital] Jurnal articles

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