title: Disparity in IL-12 release in dendritic cells and macrophages in response to Mycobacterium tuberculosis is due to use of distinct TLRs.
abstract: The control of IL-12 production from dendritic cells (DCs) and macrophages in response to Mycobacterium tuberculosis (Mtb) is not well understood. The objective of this study was to pursue the mechanism underlying our previous report that in response to Mtb infection, DCs release abundant IL-12, whereas secretion is limited in macrophages. An initial comparison of IL-12p35 and IL-12p40 gene induction showed that p35 transcription is similar in murine bone marrow-derived DCs and macrophages, but a rapid and enhanced IL-12p40 transcription occurs only in DCs. Consistent with the p40 gene transcription profile, Mtb-induced remodeling at nucleosome 1 of the p40 promoter also occurs rapidly and extensively in DCs in comparison to macrophages. Removal of IL-10 or addition of IFNgamma enhances macrophage IL-12 release to Mtb, but without affecting the kinetics of remodeling at the macrophage p40 promoter. Furthermore, we show that Mtb-induced remodeling at the p40 promoter and IL-12 release in DCs is TLR9 dependent, and in contrast, TLR2 dependent, in macrophages. Data are also presented to demonstrate that a TLR9 agonist induces quantitatively more extensive remodeling at the IL-12p40 promoter and larger IL-12 release in comparison to a TLR2 agonist. Collectively, these findings suggest that DCs and macrophages handle Mtb differently resulting in only DCs being able to engage the more efficient TLR9 pathway for IL-12 gene induction. Our results also imply that TLR2 signaling is not a good inducer of IL-12, supporting the increasingly strong paradigm that TLR2 favors Th2 responses.
authors.affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07101, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pompei
authors.forename: Sihyug
authors.initials: S
authors.lastname: Jang
authors.forename: Beata
authors.initials: B
authors.lastname: Zamlynny
authors.forename: Sharada
authors.initials: S
authors.lastname: Ravikumar
authors.forename: Amanda
authors.initials: A
authors.lastname: McBride
authors.forename: Somia Perdow
authors.initials: SP
authors.lastname: Hickman
authors.forename: Padmini
authors.initials: P
authors.lastname: Salgame
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011401:Promoter Regions, Genetic; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D053762:Interleukin-12 Subunit p40; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases