Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Animals
-
Antigens, Differentiation / genetics
-
Antigens, Differentiation / physiology*
-
Bone Marrow Cells / immunology
-
Bone Marrow Cells / metabolism
-
Cell Line, Tumor
-
Cells, Cultured
-
Chlamydophila pneumoniae / growth & development
-
Chlamydophila pneumoniae / immunology*
-
DNA-Binding Proteins / deficiency
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / physiology*
-
Humans
-
Interferon Type I / physiology*
-
Interferon-alpha / biosynthesis
-
Interferon-alpha / genetics
-
Interferon-gamma / biosynthesis*
-
Interferon-gamma / genetics
-
Interleukin Receptor Common gamma Subunit
-
Intracellular Fluid / immunology*
-
Intracellular Fluid / microbiology
-
Macrophages / immunology
-
Macrophages / metabolism
-
Membrane Glycoproteins / deficiency
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / physiology*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myeloid Differentiation Factor 88
-
NF-kappa B / metabolism
-
NF-kappa B / physiology
-
RNA, Messenger / biosynthesis
-
Receptors, Cell Surface / deficiency
-
Receptors, Cell Surface / genetics
-
Receptors, Cell Surface / physiology*
-
Receptors, Immunologic / deficiency
-
Receptors, Immunologic / genetics
-
Receptors, Immunologic / physiology*
-
Receptors, Interleukin-7 / deficiency
-
Receptors, Interleukin-7 / genetics
-
Receptors, Interleukin-7 / physiology
-
STAT1 Transcription Factor
-
Signal Transduction / genetics
-
Signal Transduction / immunology*
-
Toll-Like Receptor 2
-
Toll-Like Receptor 4
-
Toll-Like Receptor 9
-
Toll-Like Receptors
-
Trans-Activators / deficiency
-
Trans-Activators / genetics
-
Trans-Activators / physiology*
-
eIF-2 Kinase / physiology
Substances
-
Adaptor Proteins, Signal Transducing
-
Antigens, Differentiation
-
DNA-Binding Proteins
-
IL2RG protein, human
-
Il2rg protein, mouse
-
Interferon Type I
-
Interferon-alpha
-
Interleukin Receptor Common gamma Subunit
-
MYD88 protein, human
-
Membrane Glycoproteins
-
Myd88 protein, mouse
-
Myeloid Differentiation Factor 88
-
NF-kappa B
-
RNA, Messenger
-
Receptors, Cell Surface
-
Receptors, Immunologic
-
Receptors, Interleukin-7
-
STAT1 Transcription Factor
-
STAT1 protein, human
-
Stat1 protein, mouse
-
TLR2 protein, human
-
TLR4 protein, human
-
TLR9 protein, human
-
Toll-Like Receptor 2
-
Toll-Like Receptor 4
-
Toll-Like Receptor 9
-
Toll-Like Receptors
-
Trans-Activators
-
Interferon-gamma
-
eIF-2 Kinase