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Kamthong, P.J. et al.

Inhibitor of nuclear factor-kappaB induction by cAMP antagonizes interleukin-1-induced human macrophage-colony-stimulating-factor expression.

We have recently reported that interleukin-1alpha (IL-1alpha) can induce human macrophage colony-stimulating factor (M-CSF) expression through nuclear factor kappaB (NF-kappaB) activation, and treatment of human pancreatic MIA PaCa-2 cancer cells with forskolin or cAMP attenuated the NF-kappaB activation as well as M-CSF expression. In this study, we have further investigated the mechanism of cAMP attenuation. MIA PaCa-2 cells were incubated with forskolin or dibutyryl-cAMP and then stimulated with IL-1 for 1 h. Cell lysates were immunoprecipitated by anti-inhibitory kappaB (IkappaB) kinase-beta (IKKbeta) antibody and the immune complex assayed for kinase activity using recombinant inhibitor of NF-kappaB (IkappaBalpha) as substrate. The levels of IKKbeta in the respective cellular proteins were measured by subsequent Western blot. The results show that the level of IKK protein remains constant in the presence of cAMP, forskolin and/or IL-1, whereas IKK activity was robustly stimulated by IL-1. Nonetheless, dibutyryl-cAMP or forskolin did not affect the IKK activation induced by IL-1. This experiment suggests that elevated cAMP has no effect on IKK activity. IkappaBalpha protein level decreased markedly in IL-1-treated cells compared with the untreated. By contrast, cells treated with cAMP or forskolin possessed discernibly higher IkappaBalpha levels. In addition, we observed that forskolin potentiated and prolonged the IL-1- induced IkappaBalpha mRNA levels, whereas it did not stabilize the IkappaBalpha mRNA message. Wholly, these studies indicate that elevated cAMP antagonizes IL-1- induced M-CSF transcription by up-regulating IkappaBalpha gene induction and its consequent attenuation of NF-kappaB activation.[1]

References

Inhibitor of nuclear factor-kappaB induction by cAMP antagonizes interleukin-1-induced human macrophage-colony-stimulating-factor expression. Kamthong, P.J., Wu , M. Biochem. J. (2001) [Pubmed]

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