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.
Highlights
Secretion that leads to control of the intracellular bacterial growth
To investigate which Toll-like receptor (TLR) are essential for growth control of C. pneumoniae, TLR2Ϫ/Ϫ, TLR4Ϫ/Ϫ, TLR6Ϫ/Ϫ, or TLR9Ϫ/Ϫ BMM were infected with C. pneumoniae, respectively
MyD88Ϫ/Ϫ BMM were more susceptible to C. pneumoniae (Fig. 2A) compared with WT BMM, and showed no increase in IFN-␣ and IFN-␥ mRNA levels (Fig. 2, B and C)
Summary
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؊/؊) BMM is shown in this study. Accumulation of IFN-␥ mRNA and control of C. pneumoniae growth required NF-B activation Such NF-B activation was independent of IFN-␣, STAT1, and RNA-dependent protein kinase. Upon pathogen-associated molecular pattern recognition, the intracellular domains of all known TLRs interact with the adaptor molecule myeloid differentiation factor (MyD) 88 and initiate a common signaling cascade that leads to nuclear translocation of the transcription factors NF-B and AP-1. This signaling cascade can be activated upon IL-1 or IL-18R engagement [2].
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