P. 5027-5034The 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 PAM3CSK4. 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 spirocheteS
