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Infect Immun. 2007 Oct;75(10):5027-34. Epub 2007 Jul 30.

c-Jun N-terminal kinase 1 is required for Toll-like receptor 1 gene expression in macrophages.

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1
Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, MA 01003, USA.

Abstract

The regulation of innate immune responses to pathogens occurs through the interaction of Toll-like receptors (TLRs) 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 demonstrate a mechanism of control of murine macrophage responses mediated by TLR1/2 heterodimers through c-Jun N-terminal kinase 1 (JNK1) activity. JNK controls tumor necrosis factor alpha production and TLR-mediated macrophage responses to Borrelia burgdorferi, the causative agent of Lyme disease, and the TLR1/TLR2-specific agonist PAM(3)CSK(4). JNK1, but not JNK2, activity regulates the expression of the tlr1 gene 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.

PMID:
17664270
PMCID:
PMC2044510
DOI:
10.1128/IAI.00492-07
[Indexed for MEDLINE]
Free PMC Article
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