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Systematic Evaluation of the Mitogen-Activated Protein Kinases in the Induction of iNOS by Tumor Necrosis Factor-Alpha and Interferon-Gamma*

E. D. Chan, MD; B. W. Winston, MD, FCCP; S. T. Uh, MD; L. K. Remigio; D. W. H. Riches, PhD
Author and Funding Information

*From the Division of Pulmonary Sciences, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, CO.

Correspondence to: E. D. Chan, MD, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80262



Chest. 1999;116(suppl_1):91S-92S. doi:10.1378/chest.116.suppl_1.91S
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In mouse macrophages (M⊘), priming by interferon-gamma (IFN-γ) is necessary for the activation of in-ducible nitric oxide synthase (iNOS) by tumor necrosis factor-alpha (TNF-α) or lipopolysaccharide (LPS) and subsequent production of reactive nitrogen species. The signal transduction pathway initiated by LPS and IFN-γ in iNOS induction is well established, considered to be mediated by the transcription factors nuclear factor-kappa B (NF-κB) and interferon regulatory factor (IRF)-1, respectively. However, the signal transduction pathway utilized by TNF-α in the induction of iNOS is not well characterized. Because (1) the iNOS promoter contains cis-acting elements for activation protein (AP)-1 and NF-κB transcription factors, (2) the activation of AP-1 and NF-κB are variably activated by members of the mitogen-activated protein kinase (MAPK) family members, and (3) the MAPKs are strongly activated by TNF-α, we examined the role of the MAPKs (p42mapk/erk2, p46 JNK, and p38mapk) in the induction of iNOS by TNF-α and IFN-γ. We first examined the effects of interleukin-4 (IL-4) on iNOS regulation and found that IL-4 downregulated iNOS and NO2-expression by TNF-α and IFN-γ in murine M⊘. We next investigated the effects of IFN-γ or IL-4 on the induction of the MAPKs by TNF-α and found that whereas IFN-γ augmented p42mapk/erk2 and p46 JNK activation by TNF-α, IL-4 downregulated p42mapk/erk2 and p46 JNK activation by TNF-α.


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