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 cer- tain infections or upon stimulation with cytokines such as IFN- 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, al- though pulmonary levels of IFN- 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 con- trolled by MyD88 via two pathways: NF-B activa- tion 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 ad- dition, phosphorylation of STAT1 and expression of IFN regulatory factor 1 (IRF-1) were delayed in the absence of MyD88 after C. pneumoniae infec- tion but not after IFN- stimulation. Taken to- gether, our data show that for optimal induction of iNOS during C. pneumoniae infection, the con- certed action of the MyD88-dependent transcrip- tion factors NF-B and AP-1 and of the MyD88- independent transcription factors phosphorylated STAT1 and IRF-1 is required. J. Leukoc. Biol. 84: 000-000; 2008.