Intracellular Bacterial Infection-Induced IFN- Is Critically but Not Solely Dependent on Toll-Like Receptor 4-Myeloid Differentiation Factor 88-IFN- -STAT1 Signaling

Infection of murine bone marrow-derived macrophages (BMM ) with Chlamydia pneumoniae induces IFN-dependent IFNsecretion that leads to control of the intracellular bacterial growth. Enhanced growth of C. pneumoniae in Toll-like receptor (TLR) 4 / and myeloid differentiation factor (MyD) 88 / (but not TLR2 / , TLR6 / , or TLR9 / ) BMM is shown in this study. Reduced accumulation of IFNand IFNmRNA was also observed in TLR4 / and MyD88 / -infected cells. IL-1R and IL-18R signaling did not account for differences between MyD88 / and wild-type BMM . Surprisingly, infection-induced NFB activation as well as TNF, IL-1, or IL-6 mRNA expression were all normal in TLR4 / and MyD88 / cells. Phosphorylation of the transcription factor STAT1 during bacterial infection is IFNdependent, and necessary for increased IFNmRNA accumulation and chlamydial growth control. Signaling through common cytokine receptor -chain and RNA-dependent protein kinase both mediated IFN-dependent enhancement of IFNmRNA levels. Accumulation of IFNmRNA and control of C. pneumoniae growth required NFB activation. Such NFB activation was independent of IFN, STAT1, and RNA-dependent protein kinase. In summary, C. pneumoniae-induced IFNexpression in BMM is controlled by a TLR4-MyD88-IFNSTAT1-dependent pathway, as well as by a TLR4-independent pathway leading to NFB activation. The Journal of Immunology, 2004, 172: 6345–6353.