c-Jun N-terminal kinase 1 is required for Toll-like receptor 1 gene expression in macrophages.
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.
Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, MA 01003, USA.
Hooman
H
Izadi
Amirreza T
AT
Motameni
Tonya C
TC
Bates
Elias R
ER
Olivera
Vega
V
Villar-Suarez
Ila
I
Joshi
Renu
R
Garg
Barbara A
BA
Osborne
Roger J
RJ
Davis
Mercedes
M
Rincón
Juan
J
Anguita
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D025065:Borrelia burgdorferi / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D051194:Toll-Like Receptor 1 / Q000235:genetics*
D051194:Toll-Like Receptor 1; D048055:Mitogen-Activated Protein Kinase 8