Induction of iNOS by Chlamydophila pneumoniae requires MyD88-dependent activation of JNK.
Innate immune cells produce NO via inducible NO synthase (iNOS) in response to certain infections or upon stimulation with cytokines such as IFN-gamma and TNF. NO plays an important role in host defense against intracellular bacteria including Chlamydophila pneumoniae as a result of its microbicidal activity. In MyD88-deficient mice, which succumb to C. pneumoniae infection, iNOS induction is impaired 6 days postinfection, although pulmonary levels of IFN-gamma and TNF are elevated as in wild-type mice at this time-point. Here, we demonstrate that induction of iNOS in macrophages upon C. pneumoniae infection is controlled by MyD88 via two pathways: NF-kappaB activation and phosphorylation of the MAPK JNK, which leads to the nuclear translocation of c-Jun, one of the two components of the AP-1 complex. In addition, phosphorylation of STAT1 and expression of IFN regulatory factor 1 (IRF-1) were delayed in the absence of MyD88 after C. pneumoniae infection but not after IFN-gamma stimulation. Taken together, our data show that for optimal induction of iNOS during C. pneumoniae infection, the concerted action of the MyD88-dependent transcription factors NF-kappaB and AP-1 and of the MyD88-independent transcription factors phosphorylated STAT1 and IRF-1 is required.
Rodriguez
Nuria
N
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, München, Germany.
Lang
Roland
R
Wantia
Nina
N
Cirl
Christine
C
Ertl
Tanja
T
Dürr
Susanne
S
Wagner
Hermann
H
Miethke
Thomas
T
D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002690:Chlamydia Infections / Q000276:immunology* / Q000378:metabolism; D016993:Chlamydophila pneumoniae / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
D050856:Interferon Regulatory Factor-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009573:Nitrites; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4