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Infection and Immunity, April 2001, p. 2001-2010, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2001-2010.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Induction of Inducible Nitric Oxide Synthase-NO· by Lipoarabinomannan of Mycobacterium tuberculosis Is Mediated by MEK1-ERK, MKK7-JNK, and NF-kappa B Signaling Pathways

Edward D. Chan,1,2,* Kristin R. Morris,1 John T. Belisle,3 Preston Hill,3 Linda K. Remigio,2 Patrick J. Brennan,3 and David W. H. Riches1,2

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center,1 and Program in Cell Biology, National Jewish Medical and Research Center,2 Denver, and Mycobacteria Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins,3 Colorado

Received 28 August 2000/Returned for modification 3 November 2000/Accepted 4 January 2001

Nitric oxide (NO· ) expression by inducible nitric oxide synthase (iNOS) is an important host defense mechanism against Mycobacterium tuberculosis in mononuclear phagocytes. The objective of this investigation was to examine the role of mitogen-activated protein (MAP) kinase (MAPK) and nuclear factor kappa B (NF-kappa B) signaling pathways in the regulation of iNOS and NO· by a mycobacterial cell wall lipoglycan known as mannose-capped lipoarabinomannan (ManLAM). Specific pharmacologic inhibition of the extracellular-signal-regulated kinase (ERK) or NF-kappa B pathway revealed that both these signaling cascades were required in gamma interferon (IFN-gamma )-ManLAM-induced iNOS protein and NO2- expression in mouse macrophages. Transient cotransfection of dominant-negative protein mutants of the c-Jun NH2-terminal kinase (JNK) pathway revealed that the MAP kinase kinase 7 (MKK7)-JNK cascade also mediated IFN-gamma -ManLAM induction of iNOS promoter activity whereas MKK4 did not. Overexpression of null mutant Ikappa Balpha , a potent inhibitor of NF-kappa B activation, confirmed that the Ikappa Balpha kinase (IKK)-NF-kappa B signaling pathway enhanced IFN-gamma -ManLAM-induced iNOS promoter activity. By contrast, activated p38mapk inhibited iNOS induction. These results indicate that combined IFN-gamma and ManLAM stimulation induced iNOS and NO· expression and that MEK1-ERK, MKK7-JNK, IKK-NF-kappa B, and p38mapk signaling pathways play important regulatory roles.

* Corresponding author. Mailing address: K613e, Goodman Building, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Phone: (303) 398-1491. Fax: (303) 398-1806. E-mail: chane{at}njc.org.

Infection and Immunity, April 2001, p. 2001-2010, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2001-2010.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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