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Infection and Immunity, April 2001, p. 2001-2010, Vol. 69, No. 4
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
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-
B Signaling Pathways
B
(NF-
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-
B pathway revealed that both these signaling cascades were
required in gamma interferon (IFN-
)-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-
-ManLAM
induction of iNOS promoter activity whereas MKK4 did not.
Overexpression of null mutant I
B
, a potent inhibitor of NF-
B
activation, confirmed that the I
B
kinase (IKK)-NF-
B signaling
pathway enhanced IFN-
-ManLAM-induced iNOS promoter activity. By
contrast, activated p38mapk inhibited iNOS
induction. These results indicate that combined IFN-
and ManLAM
stimulation induced iNOS and NO· expression and that
MEK1-ERK, MKK7-JNK, IKK-NF-
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.
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