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Published online before print March 14, 2007

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(Journal of Leukocyte Biology. 2007;81:1591-1598.)
© 2007 by Society for Leukocyte Biology

Role of IRAK4 and IRF3 in the control of intracellular infection with Chlamydia pneumoniae

Christian Trumstedt^*, Emma Eriksson^*, Anna M. Lundberg, Tang-bin Yang^*,, Zhong-qun Yan, Hans Wigzell^* and Martin E. Rottenberg^*,1

^* Microbiology and Tumor Biology Center and
Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; and
Laboratory of Space Cellular and Molecular, Institute of Space and Medico-Engineering, Beijing, China

¹ Correspondence: Microbiology and Tumor Biology Center, Karolinska Institute, Nobels väg 16, 171 77 Stockholm, Sweden. E-mail: martin.rottenberg{at}ki.se

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-ß-mediated pathway, resulting in the activation of IFN regulatory factor (IRF)3. Both pathways can lead to expression of IFN-ß. TLR-dependent and -independent signals converge in the TNF receptor-associated factor 6 (TRAF6) adaptor, which mediates the activation of NF-B. Infection of murine bone marrow-derived macrophages (BMM) with Chlamydia pneumoniae induces IFN-/ß- and NF-B-dependent expression of IFN-, which in turn, will control bacterial growth. The role of IRAK4 and IRF3 in the regulation of IFN-/ß expression and NF-B activation was studied in C. pneumoniae-infected BMM. We found that levels of IFN-, IFN-ß, and IFN- 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-, and IFN- mRNA titers were observed in C. pneumoniae-infected IRF3^–/– BMM. On the contrary, IFN-ß^–/– BMM showed lower IFN- and IFN- mRNA levels and higher bacterial titers compared with WT controls. C. pneumoniae infection-induced activation of NF-B 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- and IFN- secretion and bacterial growth. IRAK4 and IRF3 are redundant for infection-induced NF-B activation, which is regulated by TRAF6.

Key Words: macrophage • IFN- • IFN-ß • IFN- • TLR • NF-B • TRAF6

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