Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-gamma-induced expression of the chemokine CXCL9 gene in mouse macrophages.
Sulindac, a non-steroidal anti-inflammatory drug, has been shown to exert an anti-tumor effect on several types of cancer. To determine the effect of sulindac on intracellular signaling pathways in host immune cells such as macrophages, we investigated the effect of the drug on interferon gamma (IFNgamma)-induced expression of signal transducer and activator of transcription 1 (STAT1) and other genes in mouse macrophage-like cell line RAW264.7 cells. Sulindac, but not aspirin or sodium salicylate, inhibited IFNgamma-induced expression of the CXC ligand 9 (CXCL9) mRNA, a chemokine for activated T cells, whereas the interferon-induced expression of CXCL10 or IFN regulatory factor-1 was not affected by sulindac. Luciferase reporter assay demonstrated that sulindac inhibited IFNgamma-induced promoter activity of the CXCL9 gene. Surprisingly, sulindac had no inhibitory effect on IFNgamma-induced STAT1 activation; however, constitutive nuclear factor kappaB activity was suppressed by the drug. These results indicate that sulindac selectively inhibited IFNgamma-inducible gene expression without inhibiting STAT1 activation.
Sakaeda
Yoshiichi
Y
Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan.
Hiroi
Miki
M
Shimojima
Takahiro
T
Iguchi
Mayumi
M
Kanegae
Haruhide
H
Ohmori
Yoshihiro
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology*; D015533:Transcriptional Activation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D013467:Sulindac; D007371:Interferon-gamma