Disparity in mycobacterium tuberculosis-induced IL-12 release in dendritic cells and macrophages is due to utilization of distinct Toll-like receptors (89.35)

Abstract

Abstract In the pursuit of understanding the molecular basis for a differential release of interleukin (IL)-12 between dendritic cells (DCs) and macrophages in response to Mycobacterium tuberculosis (Mtb), we first evaluated the expression of IL-12p35 and IL-12p40. The two cell types showed similar transcription levels of IL-12p35, while IL-12p40 mRNA was expressed in a rapid and enhanced manner only in murine bone-marrow DCs. An analysis of the remodeling at the nucleosome 1 of the IL-12p40 promoter also provided evidence of a rapid and extensive accessibility to the transcription factor NF-kB in DCs. Despite restoring the impaired Mtb-dependent release of IL-12, addition of interferon (IFN) 2 □ or removal of IL-10 did not affect the extent of remodeling in the IL-12 promoter of macrophages. By evaluating the IL-12p40 remodeling and release in knock-out mice models we demonstrate that DCs mainly rely on signaling from toll-like receptor (TLR)9 for their extensive Mtb induced IL-12 expression. Moreover the TLR9 ligand CpG induced extensive remodeling and release of IL-12p40 in comparison to a TLR2 agonist. Our work suggests a different handling of Mtb from the two cell types where TLR9 engagement occurs prevalently in DCs and leads to high expression of IL-12 and supports the rising opinion, which favors a role for TLR2 in Th2 type responses.