RT Journal Article SR Electronic T1 Sporogen, S14-95, and S-Curvularin, Three Inhibitors of Human Inducible Nitric-Oxide Synthase Expression Isolated from Fungi JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 383 OP 391 DO 10.1124/mol.63.2.383 VO 63 IS 2 A1 Ying Yao A1 Michael Hausding A1 Gerhard Erkel A1 Timm Anke A1 Ulrich Förstermann A1 Hartmut Kleinert YR 2003 UL http://molpharm.aspetjournals.org/content/63/2/383.abstract AB The induction of human inducible nitric-oxide synthase (iNOS) expression depends (among other factors) on activation of the signal transducer and activator of transcription 1 (STAT1) pathway. Therefore, the STAT1 pathway may be an appropriate target for the development of inhibitors of iNOS expression. HeLa S3 cells transiently transfected with a γ-activated site (GAS)/interferon-stimulated response element-driven reporter gene construct were used as the primary screening system. Using this system, three novel inhibitors of interferon-γ-dependent gene expression, namely, sporogen, S14-95, andS-curvularin, were isolated from differentPenicillium species. These three compounds also inhibited cytokine-induced, GAS-dependent reporter gene expression in stably transfected human A549/8-pGASLuc cells, confirming the data obtained with the above-mentioned screening system. Furthermore, in A549/8 cells, sporogen, S14-95, and S-curvularin inhibited cytokine-induced activity of the human iNOS promoter [a 16-kilobase (kb) fragment in stably transfected A549/8-pNOS2(16)Luc cells], cytokine-induced iNOS mRNA expression, and cytokine-induced nitric oxide (NO) production in a concentration-dependent manner. The proliferation of A549/8 cells, and the activity of the human eNOS promoter (a 3.5-kb fragment in stably transfected ECV-pNOS III-Hu-3500-Luc cells), were only influenced marginally by the three compounds. Sporogen, S14-95, and S-curvularin also inhibited cytokine-induced activation of STAT1α in A549/8 cells. In conclusion, sporogen, S14-95, and S-curvularin represent new transcriptionally based inhibitors of iNOS-dependent NO production, acting on the Janus tyrosine kinase-STAT pathway. These compounds may represent lead structures for the development of drugs inhibiting iNOS-dependent overproduction of NO in pathophysiological situations. The American Society for Pharmacology and Experimental Therapeutics