Cycloprodigiosin up-regulates inducible nitric oxide synthase gene expression in hepatocytes stimulated by interleukin-1beta.
The proinflammatory cytokine interleukin-1beta stimulates inducible nitric oxide synthase ( iNOS) gene expression in hepatocytes via activation of a transcription factor, nuclear factor-kappaB (NF-kappaB). Nitric oxide has diverse cytoprotective and toxic effects. Cycloprodigiosin is an anticancer drug that induces apoptosis through NF-kappaB-dependent mechanisms. This study investigated whether cycloprodigiosin influenced NF-kappaB activation and induction of iNOS by interleukin-1beta. Cycloprodigiosin alone had no effect on NO production by primary cultured rat hepatocytes. Simultaneous addition of cycloprodigiosin and interleukin-1beta markedly stimulated the induction of iNOS mRNA and protein compared with addition of interleukin-1beta alone, resulting in overproduction of NO. Cycloprodigiosin had no effect on degradation of the inhibitory subunit of NF-kappaB ( IkappaBalpha), but lessened the recovery of IkappaBalpha levels. The electrophoretic mobility shift assay revealed that cycloprodigiosin caused an increase of NF-kappaB activation. Consistent with this observation, cycloprodigiosin promoted the translocation of p65 (a subunit of NF-kappaB) to the nucleus. Furthermore, this drug enhanced expression of the type 1 interleukin-1 receptor, and this action showed similar concentration-dependence to its induction of iNOS. These results indicate that cycloprodigiosin up-regulates the induction of iNOS by increasing NF-kappaB activation, at least partly through enhancement of type 1 interleukin-1 receptor expression. By regulating the expression of NF-kappaB-dependent genes, such as iNOS, cycloprodigiosin administration may increase NO production during hepatic injury.[1]References
- Cycloprodigiosin up-regulates inducible nitric oxide synthase gene expression in hepatocytes stimulated by interleukin-1beta. Teshima, S., Nakanishi, H., Kamata, K., Kaibori, M., Kwon, A.H., Kamiyama, Y., Nishizawa, M., Ito, S., Okumura, T. Nitric Oxide (2004) [Pubmed]
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