Role of IRAK4 and IRF3 in the control of intracellular infection with Chlamydia pneumoniae.
TLR signal transduction involves a MyD88-mediated pathway, which leads to recruitment of the IL-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Toll/IL-1R translation initiation region domain-containing adaptor-inducing IFN-beta-mediated pathway, resulting in the activation of IFN regulatory factor (IRF)3. Both pathways can lead to expression of IFN-beta. TLR-dependent and -independent signals converge in the TNF receptor-associated factor 6 (TRAF6) adaptor, which mediates the activation of NF-kappaBeta. Infection of murine bone marrow-derived macrophages (BMM) with Chlamydia pneumoniae induces IFN-alpha/beta- and NF-kappaBeta-dependent expression of IFN-gamma, which in turn, will control bacterial growth. The role of IRAK4 and IRF3 in the regulation of IFN-alpha/beta expression and NF-kappaBeta activation was studied in C. pneumoniae-infected BMM. We found that levels of IFN-alpha, IFN-beta, and IFN-gamma mRNA were reduced in infected IRAK4(-/-) BMM compared with wild-type (WT) controls. BMM also showed an IRAK4-dependent growth control of C. pneumoniae. No increased IRF3 activation was detected in C. pneumoniae-infected BMM. Similar numbers of intracellular bacteria, IFN-alpha, and IFN-gamma mRNA titers were observed in C. pneumoniae-infected IRF3(-/-) BMM. On the contrary, IFN-beta(-/-) BMM showed lower IFN-alpha and IFN-gamma mRNA levels and higher bacterial titers compared with WT controls. C. pneumoniae infection-induced activation of NF-kappaBeta and expression of proinflammatory cytokines were shown to be TRAF6-dependent but did not require IRAK4 or IRF3. Thus, our data indicate that IRAK4, but not IRF3, controls C. pneumoniae-induced IFN-alpha and IFN-gamma secretion and bacterial growth. IRAK4 and IRF3 are redundant for infection-induced NF-kappaB activation, which is regulated by TRAF6.
Trumstedt
Christian
C
Microbiology and Tumor Biology Center, Karolinska Institute, Nobels väg 16, 171 77 Stockholm, Sweden.
Eriksson
Emma
E
Lundberg
Anna M
AM
Yang
Tang-Bin
TB
Yan
Zhong-Qun
ZQ
Wigzell
Hans
H
Rottenberg
Martin E
ME
D000818:Animals; D002478:Cells, Cultured; D002690:Chlamydia Infections / Q000276:immunology*; D016993:Chlamydophila pneumoniae / Q000502:physiology*; D004789:Enzyme Activation; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; C494233:Irf3 protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D048029:TNF Receptor-Associated Factor 6; D007371:Interferon-gamma; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse