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Type I IFN Induction in Response to Listeria monocytogenes in Human Macrophages: Evidence for a Differential Activation of IFN Regulatory Factor 3 (IRF3)¹

Institute of Veterinary Virology, University of Bern, Bern, Switzerland

Listeria monocytogenes is a prototypic bacterium for studying innate and adaptive cellular immunity as well as host defense. Using human monocyte-derived macrophages, we report that an infection with a wild-type strain, but not a listeriolysin O-deficient strain, of the Gram-positive bacterium L. monocytogenes induces expression of IFN- and a bioactive type I IFN response. Investigating the activation of signaling pathways in human macrophages after infection revealed that a wild-type strain and a hemolysin-deficient strain of L. monocytogenes activated the NF-B pathway and induced a comparable TNF response. p38 MAPK and activating transcription factor 2 were phosphorylated following infection with either strain, and IFN- gene expression induced by wild-type L. monocytogenes was reduced when p38 was inhibited. However, neither IFN regulatory factor (IRF) 3 translocation to the nucleus nor posttranslational modifications and dimerizations were observed after L. monocytogenes infection. In contrast, vesicular stomatitis virus and LPS triggered IRF3 activation and signaling. When IRF3 was knocked down using small interfering RNA, a L. monocytogenes-induced IFN- response remained unaffected whereas a vesicular stomatitis virus-triggered response was reduced. Evidence against the possibility that IRF7 acts in place of IRF3 is provided. Thus, we show that wild-type L. monocytogenes induced an IFN- response in human macrophages and propose that this response involves p38 MAPK and activating transcription factor 2. Using various stimuli, we show that IRF3 is differentially activated during type I IFN responses in human macrophages.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants 3200-665036 and 3200B0-105642 of the Swiss National Science Foundation (to T.W.J.).

² Address correspondence and reprint requests to Dr. Thornik Reimer, Institute of Veterinary Virology, University of Bern, Laenggassstrasse 122, Bern, Switzerland. E-mail address: reimer{at}ivv.unibe.ch

³ Abbreviations used in this paper: LLO, listeriolysin O; ATF, activating transcription factor; DAPI, 4',6'-diamidino-2-phenylindole; IRF, interferon regulatory factor; hly, hemolysin; LMB, leptomycin B; MDM, monocyte-derived macrophages; MOI, multiplicity of infection; Mx1, myxovirus resistance 1 (gene/protein); NTL, nuclear translocation; p.i., postinfection; PRD, positive regulatory domain; siRNA, small interfering RNA; TBK, TANK-binding kinase; VSV, vesicular stomatitis virus.

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				T. Reimer, M. Brcic, M. Schweizer, and T. W. Jungi poly(I:C) and LPS induce distinct IRF3 and NF-{kappa}B signaling during type-I IFN and TNF responses in human macrophages J. Leukoc. Biol., May 1, 2008; 83(5): 1249 - 1257. [Abstract] [Full Text] [PDF]