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Protein kinase Cdelta activation by interleukin-1beta stabilizes inducible nitric-oxide synthase mRNA in pancreatic beta-cells.
J Biol Chem 2001; 276(7):5368-74JB

Abstract

Exposure of pancreatic islets to cytokines such as interleukin (IL)-1beta induces a variety of proinflammatory genes including type II nitric-oxide synthase (iNOS) which produces nitric oxide (NO). NO is thought to be a major cause of islet beta-cell dysfunction and apoptotic beta-cell death, which results in type I diabetes. Since protein kinase C (PKC) mediates some of the actions of cytokines in other cell types, our aim was to assess the role of PKC in IL-1beta-induced iNOS expression in pancreatic beta-cells. PKCdelta, but not PKCalpha, was specifically activated in the rat INS-1 beta-cell line by IL-1beta as assessed by membrane translocation. Moreover, iNOS expression and NO production were significantly attenuated by the PKCdelta specific inhibitor rottlerin and overexpression of a PKCdelta kinase-dead mutant protein. Conversely, overexpression of PKCdelta wild type protein significantly potentiated this response. These results were confirmed at the mRNA level by reverse transcriptase-polymerase chain reaction. However, a role at the level of transcriptional regulation appeared unlikely, since PKCdelta was not required for the activation of NF-kappaB, activating protein 1, and activating transcription factor 2 signaling pathways in response to IL-1beta. There was, however, a significant increase in iNOS mRNA stability mediated by PKCdelta wild type, while PKCdelta kinase-dead acted reciprocally, reducing iNOS mRNA stability. The results indicate that, in addition to transcriptional activation, mRNA stabilization is a key component of the mechanism by which IL-1beta stimulates iNOS expression in beta-cells and that PKCdelta plays an essential role in this process. PKCdelta activation may therefore have significant consequences with regard to cellular function and viability when beta-cells are exposed to IL-1beta and potentially other cytokines.

Authors+Show Affiliations

Garvan Institute of Medical Research, St. Vincents Hospital, 384 Victoria St, Darlinghurst, Sydney, 2010, Australia.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11087760

Citation

Carpenter, L, et al. "Protein Kinase Cdelta Activation By Interleukin-1beta Stabilizes Inducible Nitric-oxide Synthase mRNA in Pancreatic Beta-cells." The Journal of Biological Chemistry, vol. 276, no. 7, 2001, pp. 5368-74.
Carpenter L, Cordery D, Biden TJ. Protein kinase Cdelta activation by interleukin-1beta stabilizes inducible nitric-oxide synthase mRNA in pancreatic beta-cells. J Biol Chem. 2001;276(7):5368-74.
Carpenter, L., Cordery, D., & Biden, T. J. (2001). Protein kinase Cdelta activation by interleukin-1beta stabilizes inducible nitric-oxide synthase mRNA in pancreatic beta-cells. The Journal of Biological Chemistry, 276(7), pp. 5368-74.
Carpenter L, Cordery D, Biden TJ. Protein Kinase Cdelta Activation By Interleukin-1beta Stabilizes Inducible Nitric-oxide Synthase mRNA in Pancreatic Beta-cells. J Biol Chem. 2001 Feb 16;276(7):5368-74. PubMed PMID: 11087760.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase Cdelta activation by interleukin-1beta stabilizes inducible nitric-oxide synthase mRNA in pancreatic beta-cells. AU - Carpenter,L, AU - Cordery,D, AU - Biden,T J, Y1 - 2000/11/21/ PY - 2000/11/23/pubmed PY - 2001/6/29/medline PY - 2000/11/23/entrez SP - 5368 EP - 74 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 276 IS - 7 N2 - Exposure of pancreatic islets to cytokines such as interleukin (IL)-1beta induces a variety of proinflammatory genes including type II nitric-oxide synthase (iNOS) which produces nitric oxide (NO). NO is thought to be a major cause of islet beta-cell dysfunction and apoptotic beta-cell death, which results in type I diabetes. Since protein kinase C (PKC) mediates some of the actions of cytokines in other cell types, our aim was to assess the role of PKC in IL-1beta-induced iNOS expression in pancreatic beta-cells. PKCdelta, but not PKCalpha, was specifically activated in the rat INS-1 beta-cell line by IL-1beta as assessed by membrane translocation. Moreover, iNOS expression and NO production were significantly attenuated by the PKCdelta specific inhibitor rottlerin and overexpression of a PKCdelta kinase-dead mutant protein. Conversely, overexpression of PKCdelta wild type protein significantly potentiated this response. These results were confirmed at the mRNA level by reverse transcriptase-polymerase chain reaction. However, a role at the level of transcriptional regulation appeared unlikely, since PKCdelta was not required for the activation of NF-kappaB, activating protein 1, and activating transcription factor 2 signaling pathways in response to IL-1beta. There was, however, a significant increase in iNOS mRNA stability mediated by PKCdelta wild type, while PKCdelta kinase-dead acted reciprocally, reducing iNOS mRNA stability. The results indicate that, in addition to transcriptional activation, mRNA stabilization is a key component of the mechanism by which IL-1beta stimulates iNOS expression in beta-cells and that PKCdelta plays an essential role in this process. PKCdelta activation may therefore have significant consequences with regard to cellular function and viability when beta-cells are exposed to IL-1beta and potentially other cytokines. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11087760/Protein_kinase_Cdelta_activation_by_interleukin_1beta_stabilizes_inducible_nitric_oxide_synthase_mRNA_in_pancreatic_beta_cells_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11087760 DB - PRIME DP - Unbound Medicine ER -