Induction of Inducible Nitric Oxide Synthase-NO· by Lipoarabinomannan ofMycobacterium tuberculosisIs Mediated by MEK1-ERK, MKK7-JNK, and NF-κB Signaling Pathways

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Abstract
Nitric oxide (NO· ) expression by inducible nitric oxide synthase (iNOS) is an important host defense mechanism againstMycobacterium tuberculosisin mononuclear phagocytes. The objective of this investigation was to examine the role of mitogen-activated protein (MAP) kinase (MAPK) and nuclear factor κB (NF-κB) 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-κB pathway revealed that both these signaling cascades were required in gamma interferon (IFN-γ)-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-γ–ManLAM induction of iNOS promoter activity whereas MKK4 did not. Overexpression of null mutant IκBα, a potent inhibitor of NF-κB activation, confirmed that the IκBα kinase (IKK)–NF-κB signaling pathway enhanced IFN-γ–ManLAM-induced iNOS promoter activity. By contrast, activated p38mapkinhibited iNOS induction. These results indicate that combined IFN-γ and ManLAM stimulation induced iNOS and NO· expression and that MEK1-ERK, MKK7-JNK, IKK–NF-κB, and p38mapksignaling pathways play important regulatory roles.

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