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Blood, 1 August 2006, Vol. 108, No. 3, pp. 965-973.
Prepublished online as a Blood First Edition Paper on April 6, 2006; DOI 10.1182/blood-2005-12-5046.


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Submitted December 21, 2005
Accepted March 21, 2006

The Wingless homologue Wnt5a and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation

Antje Blumenthal, Stefan Ehlers, Jorg Lauber, Jan Buer, Christoph Lange, Torsten Goldmann, Holger Heine, Ernst Brandt, and Norbert Reiling*

Division of Molecular Infection Biology, Research Center Borstel (RCB), Borstel, Germany
Department of Mucosal Immunity, The German Research Center for Biotechnology (GBF), Braunschweig, Germany
Department of Mucosal Immunity, The German Research Center for Biotechnology (GBF), Braunschweig, Germany; Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany
Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
Division of Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany
Divison of Innate Immunity, Research Center Borstel, Borstel, Germany
Division of Biological Chemistry, Research Center Borstel, Borstel, Germany

* Corresponding author; email: nreiling{at}fz-borstel.de.

Microarray-assisted gene expression screens of human macrophages revealed Wnt5a, a homologue of Wingless, a key regulator of Drosophila melanogaster embryonic segmentation and patterning, to be consistently upregulated following stimulation with different mycobacterial species and conserved bacterial structures. The expression of Wnt5a required TLR signaling and NF-{kappa}B activation, which identifies a novel induction pathway for a Wingless homologue. We show that human peripheral blood mononuclear cells express the Wnt5a receptor Frizzled-5 (Fzd5). Both, Wnt5a and Fzd5, were also detected in granulomatous lesions in the lungs of M. tuberculosis infected patients. Functional studies showed that Wnt5a and Fzd5 regulate the microbially induced IL-12 response of antigen presenting cells and IFN-{gamma} production by mycobacterial antigen-stimulated T cells. Our findings implicate the evolutionarily conserved Wnt/Frizzled signaling system in bridging innate and adaptive immunity to infections.


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