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 (IFN gamma)-induced expression of signal transducer and activator of transcription I (STATI) and other genes in mouse macrophage-like cell line RAW264.7 cells. Sulindac, but not aspirin or sodium salicylate, inhibited IFN gamma-induced expression of the CXC ligand 9 (CXCL9) mRNA, a chemokine for activated T cells, whereas the interferon-induced expression of CXCL1O or IFN regulatory factor-1 was not affected by sulindac. Luciferase reporter assay demonstrated that sulindac inhibited IFN gamma-induced promoter activity of the CXCL9 gene. Surprisingly, sulindac had no inhibitory effect on IFN gamma-induced STATI activation; however, constitutive nuclear factor kappa B activity was suppressed by the drug. These results indicate that sulindac selectively inhibited IFN gamma-inducible gene expression without inhibiting STATI activation. (c) 2006 Elsevier Inc. All rights reserved.