期刊
JOURNAL OF HEPATOLOGY
卷 40, 期 4, 页码 616-623出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2003.12.018
关键词
interleukin-1 beta; inducible nitric oxide synthase; type 1 IL-1 receptor; nuclear factor-KB; phosphatidy-linositol 3-kinase/Akt
Background/Aims: Nuclear translocation and DNA binding of NF-kappaB is essential, as interleukin-1beta (IL-1beta) stimulates the induction of inducible nitric oxide synthase (iNOS) gene expression in hepatocytes. However, recent evidence indicates that the activation of NF-kappaB is not sufficient to induce the NF-kappaB-dependent transcription, and the existence of a second signaling is postulated. Methods: Primary cultured hepatocytes were treated with IL-1beta, and the expression of iNOS and type 1 IL-1 receptor (IL-1R1) was analyzed in the presence of antisense of IL-1R1, phosphatidylinositol 3-kinase (PI3K) inhibitor, proteasome inhibitor and hypoxia. Moreover, the activities of Akt and NF-kappaB were recorded and the cotransfection was carried out. Results: Antisense experiment revealed that IL-1R1 was required for iNOS transcription. IL-1beta markedly stimulated the induction of IL-1R1, which preceded the induction of iNOS. The IL-1R1 induction was found to be PI3K/Akt-dependent but NF-kappaB-independent. The up-regulation of IL-1R1 was associated with the second activation of Akt, which accelerated the phosphorylation of NF-kappaB p65 subunit. Cotransfection experiments revealed that Alit increased the transcriptional activity of iNOS gene promoter. Conclusions: These results indicate that the up-regulation of IL-1R1 in concert with the activation of NF-kappaB is required for the transcriptional activation of iNOS gene. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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