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Uropathogenic Escherichia coli Block MyD88-Dependent and Activate MyD88-Independent Signaling Pathways in Rat Testicular Cells¹

Sudhanshu Bhushan^*, Svetlin Tchatalbachev, Jörg Klug^*, Monika Fijak^*, Charles Pineau, Trinad Chakraborty and Andreas Meinhardt^2,*

^* Department of Anatomy and Cell Biology, Unit of Reproductive Biology and Department of Medical Microbiology, Justus-Liebig-University Giessen, Giessen, Germany; and Institut National de la Santé et de la Recherche Médicale, U625, Groupe d’étude de la reproduction chez l’homme et les mammifères, Institut Fédératif de Recherche 140, Campus de Beaulieu, Rennes, France

Uropathogenic Escherichia coli (UPEC) is the most common etiological cause of urogenital tract infections and represents a considerable cause of immunological male infertility. We examined TLR 1–11 expression profiles in testicular cells and the functional response to infection with UPEC. All testicular cell types expressed mRNAs for at least two TLRs and, in particular, synthesis of TLR4 was induced in testicular macrophages (TM), Sertoli cells (SC), peritubular cells (PTC), and peritoneal macrophages (PM) after UPEC exposure. Even though MyD88-dependent pathways were activated as exemplified by phosphorylation of mitogen-activated protein kinases in TM, SC, PTC, and PM and by the degradation of IB and the nuclear translocation of NF-B in PTC and PM, treatment with UPEC did not result in secretion of the proinflammatory cytokines IL-1, IL-6, and TNF- in any of the investigated cells. Moreover, stimulated production of these cytokines by nonpathogenic commensal E. coli or LPS in PM was completely abolished after coincubation with UPEC. Instead, in SC, PTC, TM, and PM, UPEC exposure resulted in activation of MyD88-independent signaling as documented by nuclear transfer of IFN-related factor-3 and elevated expression of type I IFNs and β, IFN--inducible protein 10, MCP-1, and RANTES. We conclude that in this in vitro model UPEC can actively suppress MyD88-dependent signaling at different levels to prevent proinflammatory cytokine secretion by testicular cells. Thus, testicular innate immune defense is shifted to an antiviral-like MyD88-independent response.

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 study was supported by a grant of the Deutsche Forschungsgemeinschaft (Clinical Research Unit KFO 181), the German National Genome Research Network (NGFN IE-S08T03), and a fellowship from Dr. Heinz-Horst Deichmann to S.B.

² Address correspondence and reprint requests to Dr. Andreas Meinhardt, Department of Anatomy and Cell Biology, Justus-Liebig-University Giessen, Aulweg 123, 35385 Giessen, Germany. E-mail address: andreas.meinhardt{at}anatomie.med.uni-giessen.de

³ Abbreviations used in this paper: UPEC, uropathogenic Escherichia coli; DC, dendritic cell; IP-10, IFN--induced protein 10; IRF-3, IFN-regulated factor 3; LC, Leydig cell; MAP, mitogen-activated protein; MOI, multiplicity of infection; NOD, nucleotide-binding oligomerization domain; NPEC, nonpathogenic E. coli; PM, peritoneal macrophage; PTC, peritubular cell; SC, Sertoli cell; TM, testicular macrophage; TRAM, TRIF-related adapter molecule; TRIF, Toll/IL-1R domain-containing adapter inducing IFN-β.

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