Key points are not available for this paper at this time.
Treatment of mouse astrocyte cultures with combined interleukin (IL)-1α and tumor necrosis factor (TNF)-α induced expression of inducible nitric-oxide synthase (iNOS), resulting in sustained release of large amounts of nitric oxide, whereas TNF-α and IL-1α individually were unable to induce iNOS expression in astrocytes. The role of MAPK cascades and of NF-κB activation in the early intracellular signal transduction involved in iNOS transcription in TNF-α/IL-1α-stimulated astrocytes was investigated. TNF-α and IL-1α activated all p42/44MAPK, p38MAPK, and p54JNK pathways as determined by immunoprecipitation kinase assays using specific antibodies and substrates. The p38MAPK pathway is specifically involved in TNF-α/IL-1α-induced iNOS expression, since iNOS protein and nitric oxide release in the presence of a specific inhibitor of p38MAPK, 4-(4-fluorophenyl)-2–2-(4-hydroxyphenyl)-5-(4-pyridyl)-imidazole (FHPI), were dramatically diminished. In contrast, PD98059, a specific inhibitor of MEK1 had no effect on iNOS expression. p38MAPKdid not couple NF-κB to iNOS transcription, but NF-κB had a clear role in iNOS transcription regulation. Northern blot analysis showed that the p38MAPK pathway controlled iNOS expression at the transcriptional level, since iNOS mRNA was reduced in the presence of FHPI in TNF-α/IL-1α-stimulated astrocytes. iNOS expression was investigated with TNF receptor (TNFR)-1- and TNFR-2-deficient mice. The TNF-α activity in TNF-α/IL-1α-stimulated astrocytes was exclusively mediated through TNFR-1, most likely because TNFR-2-mediated signals in astrocytes did not connect to the p38MAPK pathway. These data suggest that TNF-α/IL-1α-induced iNOS expression depends on a yet undetermined second pathway in addition to p38MAPK. Treatment of mouse astrocyte cultures with combined interleukin (IL)-1α and tumor necrosis factor (TNF)-α induced expression of inducible nitric-oxide synthase (iNOS), resulting in sustained release of large amounts of nitric oxide, whereas TNF-α and IL-1α individually were unable to induce iNOS expression in astrocytes. The role of MAPK cascades and of NF-κB activation in the early intracellular signal transduction involved in iNOS transcription in TNF-α/IL-1α-stimulated astrocytes was investigated. TNF-α and IL-1α activated all p42/44MAPK, p38MAPK, and p54JNK pathways as determined by immunoprecipitation kinase assays using specific antibodies and substrates. The p38MAPK pathway is specifically involved in TNF-α/IL-1α-induced iNOS expression, since iNOS protein and nitric oxide release in the presence of a specific inhibitor of p38MAPK, 4-(4-fluorophenyl)-2–2-(4-hydroxyphenyl)-5-(4-pyridyl)-imidazole (FHPI), were dramatically diminished. In contrast, PD98059, a specific inhibitor of MEK1 had no effect on iNOS expression. p38MAPKdid not couple NF-κB to iNOS transcription, but NF-κB had a clear role in iNOS transcription regulation. Northern blot analysis showed that the p38MAPK pathway controlled iNOS expression at the transcriptional level, since iNOS mRNA was reduced in the presence of FHPI in TNF-α/IL-1α-stimulated astrocytes. iNOS expression was investigated with TNF receptor (TNFR)-1- and TNFR-2-deficient mice. The TNF-α activity in TNF-α/IL-1α-stimulated astrocytes was exclusively mediated through TNFR-1, most likely because TNFR-2-mediated signals in astrocytes did not connect to the p38MAPK pathway. These data suggest that TNF-α/IL-1α-induced iNOS expression depends on a yet undetermined second pathway in addition to p38MAPK. Nitric oxide (NO) 1The abbreviations used are: NO, nitric oxide; NOS, nitric-oxide synthase(s); iNOS, inducible nitric-oxide synthase; TNF-α, tumor necrosis factor-α; TNFR, tumor necrosis factor receptor; IL-1α, interleukin 1α; MAPK, mitogen-activated protein kinase; JNK, c-jun amino-terminal kinase; ERK, extracellular signal-regulated protein kinase; MBP, myelin basic protein; ATF-2, activating transcription factor-2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MCP-1, monocyte chemoattractant protein 1; PAGE, polyacrylamide gel electrophoresis; FHPI, 4-(4-fluorophenyl)-2–2-(4-hydroxyphenyl)-5-(4-pyridyl)-imidazole; GST, glutathione S-transferase; PMSF, phenylmethylsulfonyl fluoride; DTT, dithiothreitol; IFN-γ, interferon γ. 1The abbreviations used are: NO, nitric oxide; NOS, nitric-oxide synthase(s); iNOS, inducible nitric-oxide synthase; TNF-α, tumor necrosis factor-α; TNFR, tumor necrosis factor receptor; IL-1α, interleukin 1α; MAPK, mitogen-activated protein kinase; JNK, c-jun amino-terminal kinase; ERK, extracellular signal-regulated protein kinase; MBP, myelin basic protein; ATF-2, activating transcription factor-2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MCP-1, monocyte chemoattractant protein 1; PAGE, polyacrylamide gel electrophoresis; FHPI, 4-(4-fluorophenyl)-2–2-(4-hydroxyphenyl)-5-(4-pyridyl)-imidazole; GST, glutathione S-transferase; PMSF, phenylmethylsulfonyl fluoride; DTT, dithiothreitol; IFN-γ, interferon γ. is a short lived molecule that mediates a wide range of biologic effects. It acts as an intercellular messenger (for reviews, see Refs. 1Bredt D.S. Snyder S.H. Annu. Rev. Biochem. 1994; 63: 175-195Crossref PubMed Scopus (2129) Google Scholar, 2Lowenstein C.J. Snyder S.H. Cell. 1992; 70: 705-707Abstract Full Text PDF PubMed Scopus (737) Google Scholar, 3Schmidt H.H.W. Walter U. Cell. 1994; 78: 919-925Abstract Full Text PDF PubMed Scopus (1495) Google Scholar) and plays a role in neurotransmission, antimicrobial defense, and vascular homeostasis (4Nathan C. FASEB J. 1992; 6: 3051-3064Crossref PubMed Scopus (4145) Google Scholar, 5Moncada S. Higgs A. N. Engl. J. Med. 1993; 329: 2002-2012Crossref PubMed Scopus (5704) Google Scholar). The enzymes responsible for NO synthesis, nitric-oxide synthases (NOS), convert l-arginine tol-citrulline and NO. In the brain, three genes encode NO synthase isoforms, with significant differences in their regulation (6Nathan C. Xie Q.-W. Cell. 1994; 78: 915-918Abstract Full Text PDF PubMed Scopus (2741) Google Scholar, 7Murphy S. 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Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar) and A. Gaestel M. N. Lee J.F. W. Biochem. 1997; PubMed Scopus Google Scholar). The the role of p38MAPK in the regulation of iNOS expression. The that a pathway iNOS expression signals by combined TNF-α and IL-1α in mouse astrocytes. p38MAPK activation is but not since by TNF-α or IL-1α activated p38MAPK but was unable to induce iNOS The signal acts since iNOS transcription is by protein The TNF and have been reported J. W. H. Y. P. F. A. R. M. H. 1993; PubMed Scopus Google Scholar, K. T. A. K. M. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, A. H. W. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). were after were mouse as H. PubMed Scopus Google Scholar). were and of the in a on and to of in for at was through the of a were at and in 1 were in with cells in the was with a cultures astrocytes as determined by protein kinase astrocytes were by a in antibodies p38MAPK and p42/44MAPK were antibodies p38MAPK, glutathione and were was was The specific FHPI was The specific inhibitor was mouse TNF-α was by H. J. B. and U. IL-1α was a R. Protein was phenylmethylsulfonyl and were and myelin basic protein were and were and to in were for with cytokines or and cell was as by and P. N. Biochem. PubMed Scopus Google Scholar). of were through to and by The were in 1 for 1 and at in by and with to were iNOS iNOS and The was were for at 1 and for at 1 and to in were with and in of 2 1 PMSF, 1 for on cell were and the were Protein were determined using the with as a of cell of protein in were by or and to The were with in and with specific for 2 and with for 1 at were revealed using the range were used as to of protein were three for at with of protein and with 1 of and antibodies for 1 at under were to to of protein for The were with and and were for at in of kinase 2 DTT, of and 1 of or were by the addition of and were and by or The were and was using a were in at and with cytokines, and were at the The of a of NO was used as a of NO of were with of and for at and the was at with a using as a were as PubMed Scopus Google Scholar), with or astrocytes were with of A 1 PMSF, were and cells were to on for The were at for at the were and the of the was The were in of 1 for and on for 1 with were at for at and of 1 PMSF, were to the the The protein was with the protein with as a were at assays were by of with 2 of and of in of binding DTT, for at A with the was used as a to specific NF-κB binding were with using kinase; of were to the for at were using polyacrylamide The expression of iNOS protein in mouse astrocyte cultures was first in by using a specific A the of iNOS expression in astrocyte by combined iNOS protein was first at a after and were after 24 and the of iNOS expression and NO astrocyte cultures were with the cell were and were determined by a of in the with the iNOS protein expression was found 1 a pathway mediates the TNF-α/IL-1α-stimulated iNOS a specific FHPI, was used to S. D. D. M.J. S.W. J.E. J.L. 1994; PubMed Scopus Google Scholar). in 1 C, of astrocytes with FHPI reduced the TNF-α/IL-1α-induced iNOS protein expression to at the a the NO release determined the in the after was by to 1 In contrast, iNOS expression 24 after was only by the with PD98059, a specific inhibitor of the pathway 1 a the NO release after was reduced by in the presence of of PD98059, a treatment that the MEK1 pathway L. A.R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar). The FHPI of the of iNOS expression was determined in astrocytes that had been for with of p38MAPK inhibitor and iNOS expression was in a with a of about with the of FHPI determined in assays using p38MAPK not The NO in astrocyte cultures in the presence of of FHPI well with the iNOS protein expression 2 The of NO release by treatment at about at a of about The expression of iNOS had been to be regulated at the transcriptional M.J.M. Velasco M. Martı́n-Sanz P. Boscá L. J. Biol. Chem. 1996; 271: 30114-30120Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar), but the on p38MAPK activation and the presence of in the of the iNOS mRNA that a regulation at the the of the regulation of iNOS expression by the p38MAPK iNOS mRNA were by Northern blot analysis in TNF-α/IL-1α-stimulated astrocytes in the presence or the of p38MAPK TNF-α and IL-1α treatment in a of the iNOS The was first at a at and had after 24 of the cells with FHPI in a in iNOS after and only were at the and The that iNOS mRNA are well with of iNOS protein expression in the presence of FHPI, the inhibitor a in iNOS protein expression 2 These a transcriptional control of iNOS by p38MAPK. for a activity of FHPI on iNOS the Northern were for inducible the The induction of TNF-α/IL-1α-stimulated transcription was found of FHPI treatment of the cells and therefore be controlled by signal pathways of p38MAPK activity the of protein by the astrocytes was by FHPI treatment in a with an of the that the mRNA were that p38MAPK control of release at a not response in cells after showed that the of iNOS transcription well with the determined in the and NO release with of iNOS expression at the transcriptional the induction of iNOS mRNA transcription by treatment on protein synthesis, the astrocytes were in the presence of or 1 the of the The cells were after of at a in control cultures iNOS transcription was at 1 and induction of iNOS transcription as by Northern blot analysis whereas transcription of and was not by the the role of the TNF-α and IL-1α in the iNOS expression, astrocyte cultures were with TNF-α, IL-1α, or combined for 24 were and by and were for iNOS protein by iNOS expression was after combined treatment but not after treatment with TNF-α or IL-1α or after by used as control Northern analysis showed that the astrocytes to TNF-α and to IL-1α with induced transcription of the but iNOS transcription the combined activity of cytokines a combined is for NO release after had that the differences TNF-α, IL-1α, combined and are not to different of NO release to was not to for TNF-α or IL-1α to induce the release of NO by are activated by which the and in the or of p42/44MAPK, p38MAPK, or cytokines, including TNF-α and IL-1α have been to different the role of the different MAPK pathways in the and combined TNF-α/IL-1α-induced iNOS expression, immunoprecipitation kinase assays were were with TNF-α, IL-1α, combined and for p38MAPK, p42/44MAPK, and the with specific and kinase assays were using and MBP, or as specific The were by and the in the was determined p38MAPK in astrocytes a activity as early as and 1 after the of TNF-α treatment The p42/44MAPK and p54JNK activity were with p38MAPK, about after IL-1α treatment induced a activation of p38MAPK, p42/44MAPK, and to with TNF-α The induction of iNOS expression in the astrocytes combined TNF-α and IL-1α yet TNF-α and IL-1α were to p38MAPK. the treatment with cytokines combined did not p38MAPK in a or different TNF-α or IL-1α the and of the activation of p42/44MAPK and p54JNK were not by the presence of combined p38MAPK and p54JNK are activated by stress factors such as in was therefore used to the kinase to had a response of p38MAPK and p54JNK activation by first at The therefore were at which a activation of p38MAPK and was to the p42/44MAPK pathway thought to be under the control of or factor The were in with the of of p38MAPK and of astrocytes were with amounts of protein were by and to and the of p38MAPK and p42/44MAPK was by using specific p38MAPK or p42/44MAPK antibodies that the phosphorylated p38MAPK and p42/44MAPK in TNF-α, IL-1α, and combined induced a in p38MAPK and p42/44MAPK that was clearly as early as and The signals were reduced after and were at after transcription such as have been in iNOS expression (14Lowenstein C.J. Alley E.W. Raval P. Snowman A.M. Snyder S.H. Russell S.W. Murphy W.J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 9730-9734Crossref PubMed Scopus (1005) Google Scholar, 16Dı́az-Guerra M.J.M. Velasco M. Martı́n-Sanz P. Boscá L. J. Biol. Chem. 1996; 271: 30114-30120Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). NF-κB in the control of genes of the response to stress and the that p38MAPK couple the activation of NF-κB to the response to cytokines and stress in astrocyte cultures was The of TNF-α, IL-1α, combined and in the presence or of FHPI on the activation of NF-κB were by assays of astrocyte using a was with all and combined cells that was in or the of p38MAPK by FHPI did not with the of in of the that p38MAPK is not involved in the of the activation and of NF-κB to TNF-α and IL-1α receptor The of TNF-α are mediated through and M. H.J. W. W. Proc. Natl. Acad. Sci. U. S. A. 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NF-κB has been reported to be involved in iNOS induction (17Dı́az-Guerra M.J.M. Bodelón O.G. Velasco M. Whelan R. Parker P.J. Boscá L. J. Biol. Chem. 1996; 271: 32028-32033Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, Q.-W. Y. C. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). It was activated by TNF-α as well as IL-1α in the astrocytes. NF-κB and p38MAPK on pathways as by the that did not with activation of S. M. M.L. K. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, H. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), and by the of that NF-κB is of p38MAPK. NF-κB a second pathway for iNOS induction. NF-κB has been reported to be important for iNOS transcription, since the of and cells with an inhibitor of NF-κB iNOS transcription M.P. Wong J.M. Ignarro L.J. Biochem. 1993; PubMed Scopus Google Scholar, W. D. J. 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Silva et al. (Sat,) studied this question.