Program in Molecular Medicine
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Immunity | Immunology of Infectious Disease | Molecular Biology
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.
innate immune responses, Toll-like receptors (TLRs), c-Jun N-terminal kinase 1 (JNK1)
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DOI of Published Version
Infect Immun. 2007 Oct;75(10):5027-34. Epub 2007 Jul 30. Link to article on publisher's site
Infection and immunity
Izadi H, Motameni AT, Bates TC, Olivera ER, Villar-Suarez V, Joshi I, Garg R, Osborne BA, Davis RJ, Rincon M, Anguita J. (2007). c-Jun N-terminal kinase 1 is required for Toll-like receptor 1 gene expression in macrophages. Davis Lab Publications. https://doi.org/10.1128/IAI.00492-07. Retrieved from https://escholarship.umassmed.edu/davis/57