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Infect. Immun. doi:10.1128/IAI.00492-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

c-Jun N-Terminal Kinase 1 is Required for toll-like receptor 1 Gene Expression in Macrophages

Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA 01003; Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223; Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605; Section of Immunobiology. Department of Medicine. University of Vermont College of Medicine. Burlington, VT 05401

^* To whom correspondence should be addressed. Email: janguita{at}vasci.umass.edu.

	Abstract

The regulation of innate immune responses to pathogens occurs through the interaction of Toll-like receptors with pathogen-associated molecular patterns, and the activation of several signaling pathways, whose contribution to the overall innate immune response to pathogens is poorly understood. We now demonstrate a mechanism of control of murine macrophage responses mediated by TLR1/2 heterodimers through JNK1 activity. JNK controls TNF production and TLR-mediated macrophage responses to Borrelia burgdorferi, the causative agent of Lyme disease, and the TLR1/TLR2 specific agonist, PAM₃CSK₄. JNK1, but not JNK2, activity regulates the expression of the tlr1 gene, both in the macrophage cell line RAW264.7, as well as in primary CD11b⁺ cells. We also show that the proximal promoter region of the human tlr1 gene contains an AP-1 binding site that is subjected to regulation by the kinase, and binds two complexes that involve the JNK substrates c-Jun, JunD and ATF-2. These results demonstrate that JNK1 regulates the response to TLR1/2 ligands and suggest a positive feedback loop that may serve to increase the innate immune response to the spirochete.