Intracellular bacterial infection-induced IFN-gamma is critically but not solely dependent on Toll-like receptor 4-myeloid differentiation factor 88-IFN-alpha beta-STAT1 signaling.
Infection of murine bone marrow-derived macrophages (BMMphi) with Chlamydia pneumoniae induces IFN-alphabeta-dependent IFN-gamma secretion 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(-/-)) BMMphi is shown in this study. Reduced accumulation of IFN-alpha and IFN-gamma mRNA 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 BMMphi. Surprisingly, infection-induced NF-kappaB activation as well as TNF-alpha, 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 IFN-alphabeta dependent, and necessary for increased IFN-gamma mRNA accumulation and chlamydial growth control. Signaling through common cytokine receptor gamma-chain and RNA-dependent protein kinase both mediated IFN-alphabeta-dependent enhancement of IFN-gamma mRNA levels. Accumulation of IFN-gamma mRNA and control of C. pneumoniae growth required NF-kappaB activation. Such NF-kappaB activation was independent of IFN-alphabeta, STAT1, and RNA-dependent protein kinase. In summary, C. pneumoniae-induced IFN-gamma expression in BMMphi is controlled by a TLR4-MyD88-IFN-alphabeta-STAT1-dependent pathway, as well as by a TLR4-independent pathway leading to NF-kappaB activation.
Rothfuchs
Antonio Gigliotti
AG
Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden.
Trumstedt
Christian
C
Wigzell
Hans
H
Rottenberg
Martin E
ME
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000254:growth & development / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D053631:Interleukin Receptor Common gamma Subunit; D007424:Intracellular Fluid / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020395:Receptors, Interleukin-7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019892:eIF-2 Kinase / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D007370:Interferon Type I; D016898:Interferon-alpha; D053631:Interleukin Receptor Common gamma Subunit; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D020395:Receptors, Interleukin-7; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D015534:Trans-Activators; D007371:Interferon-gamma; D019892:eIF-2 Kinase