Involvement of protein kinases in the induction of NO synthase II in human DLD‐1 cells

Involvement of protein kinases in the induction of NO synthase II in human DLD‐1 cells Protein phosphorylation is involved in the induction of nitric oxide synthase II (NOS II, iNOS) in several types of animal cells. Here we have investigated the possible involvement of major protein kinases in the induction of NOS II expression in human DLD‐1 cells. In DLD‐1 cells, interferon‐γ alone induced a submaximal NOS II expression; a cytokine mixture consisting of interferon‐γ, tumour necrosis factor‐α and interleukin‐1β produced maximal NOS II induction. Activators of protein kinase A (forskolin, 8‐dibutyryl‐cyclic AMP), of protein kinase C (tetradecanoylphorbol‐13‐acetate), and of protein kinase G (8‐bromo cyclic GMP) did not induce NOS II mRNA by themselves, nor did they alter NOS II mRNA induction in response to cytokines. Inhibitors of protein kinase A (compound H89), of protein kinase C (bisindolylmaleimide, chelerythrine or staurosporine), of phosphatidylinositol 3‐kinase (wortmannin), of p38 mitogen‐activated protein kinase (compound SB 203580) and of extracellular signal‐regulated kinase (compound PD 98059) also had no influence on basal or cytokine‐induced NOS II mRNA expression. Immunoprecipitation kinase assays showed no activation of extracellular signal‐regulated kinase or p38 mitogen‐activated protein kinase in cytokine‐incubated DLD‐1 cells. The c‐Jun NH2‐terminal kinase was activated by cytokines, but the most efficacious cytokine was tumour necrosis factor‐α which did not induce NOS II by itself. In contrast, the protein tyrosine kinase inhibitor tyrphostin B42 (a specific inhibitor of interferon‐γ‐activated janus kinase 2) and the protein tyrosine kinase inhibitor tyrphostin A25 both reduced CM‐induced NOS II mRNA expression in a concentration‐dependent manner. These results suggest that activation of NOS II expression in DLD‐1 cells is independent of the activities of protein kinases A, C and G, phosphatidylinositol 3‐kinase, extracellular signal regulated kinase and p38 mitogen‐activated protein kinase, but seems to require protein tyrosine kinase activity, especially the interferon‐γ‐activated janus kinase 2. British Journal of Pharmacology (1998) 123, 1716–1722; doi:10.1038/sj.bjp.0701782 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Involvement of protein kinases in the induction of NO synthase II in human DLD‐1 cells

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Publisher
Wiley
Copyright
1998 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
D.O.I.
10.1038/sj.bjp.0701782
Publisher site
See Article on Publisher Site

Abstract

Protein phosphorylation is involved in the induction of nitric oxide synthase II (NOS II, iNOS) in several types of animal cells. Here we have investigated the possible involvement of major protein kinases in the induction of NOS II expression in human DLD‐1 cells. In DLD‐1 cells, interferon‐γ alone induced a submaximal NOS II expression; a cytokine mixture consisting of interferon‐γ, tumour necrosis factor‐α and interleukin‐1β produced maximal NOS II induction. Activators of protein kinase A (forskolin, 8‐dibutyryl‐cyclic AMP), of protein kinase C (tetradecanoylphorbol‐13‐acetate), and of protein kinase G (8‐bromo cyclic GMP) did not induce NOS II mRNA by themselves, nor did they alter NOS II mRNA induction in response to cytokines. Inhibitors of protein kinase A (compound H89), of protein kinase C (bisindolylmaleimide, chelerythrine or staurosporine), of phosphatidylinositol 3‐kinase (wortmannin), of p38 mitogen‐activated protein kinase (compound SB 203580) and of extracellular signal‐regulated kinase (compound PD 98059) also had no influence on basal or cytokine‐induced NOS II mRNA expression. Immunoprecipitation kinase assays showed no activation of extracellular signal‐regulated kinase or p38 mitogen‐activated protein kinase in cytokine‐incubated DLD‐1 cells. The c‐Jun NH2‐terminal kinase was activated by cytokines, but the most efficacious cytokine was tumour necrosis factor‐α which did not induce NOS II by itself. In contrast, the protein tyrosine kinase inhibitor tyrphostin B42 (a specific inhibitor of interferon‐γ‐activated janus kinase 2) and the protein tyrosine kinase inhibitor tyrphostin A25 both reduced CM‐induced NOS II mRNA expression in a concentration‐dependent manner. These results suggest that activation of NOS II expression in DLD‐1 cells is independent of the activities of protein kinases A, C and G, phosphatidylinositol 3‐kinase, extracellular signal regulated kinase and p38 mitogen‐activated protein kinase, but seems to require protein tyrosine kinase activity, especially the interferon‐γ‐activated janus kinase 2. British Journal of Pharmacology (1998) 123, 1716–1722; doi:10.1038/sj.bjp.0701782

Journal

British Journal of PharmacologyWiley

Published: Apr 1, 1998

References

  • Tyrosine kinases are involved with the expression of inducible nitric oxide synthase in human articular chondrocytes
    Geng, Geng; Maier, Maier; Lotz, Lotz
  • Interleukin‐1 beta activates c‐jun NH2‐terminal kinase subgroup of mitogen‐activated protein kinases in mesangial cells
    Guan, Guan; Tetsuka, Tetsuka; Baier, Baier; Morrison, Morrison
  • Protein tyrosine kinase inhibitors suppress the production of nitric oxide in mixed glia, microglia‐enriched or astrocyte‐enriched cultures
    Kong, Kong; Mcmillian, Mcmillian; Maronpot, Maronpot; Hong, Hong
  • Role of interferon regulatory factor 1 in induction of nitric oxide synthase
    Martin, Martin; Nathan, Nathan; Xie, Xie

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