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Rho proteins (Rho, Rac, Cdc 42) are known to control the organization of the actin cytoskeleton as well as gene expression. Inhibition of Rho proteins by Clostridium difficile toxin B disrupted the F-actin cytoskeleton and enhanced cytokine-induced inducible nitric oxide synthase (iNOS) expression in human epithelial cells. Also specific inhibition by Y-27632 of p160ROCK, which mediates Rho effects on actin fibers, caused a disruption of the actin cytoskeleton and a superinduction of cytokine-induced iNOS expression. Accordingly, direct disruption of the actin cytoskeleton by cytochalasin D, latrunculin B, or jasplakinolide enhanced cytokine-induced iNOS expression. The transcription factor serum response factor (SRF) has been described as mediating actin cytoskeleton-dependent regulation of gene expression. Direct targets of SRF are activating protein 1 (AP1)-dependent genes. All compounds used inhibited SRF- and AP1-dependent reporter gene expression in DLD-1 cells. However, the enhancing effect of the actin cytoskeleton-disrupting compounds on human iNOS promoter activity was much less pronounced than the effect on iNOS mRNA expression. Therefore, besides transcriptional mechanisms, posttranscriptional effects seem to be involved in the regulation of iNOS expression by the above compounds. In conclusion, our data suggest that Rho protein-mediated changes of the actin cytoskeleton negatively modulate the expression of human iNOS.