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* Department of Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07101;
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140; and
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19410
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 IFN
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant AI055377.
2 L.P. and S.J. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Padmini Salgame, Department of Medicine, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Medical Science Building, Room A-902, Newark, NJ 07101. E-mail address: salgampa{at}umdnj.edu
4 Abbreviations used in this paper: Mtb, Mycobacterium tuberculosis; DC, dendritic cell; KO, knockout; DKO, double KO; ChART, chromatin accessibility; Ct, cycle threshold; WT, wild type; PIM, phosphatidyl-myo-inositol mannoside; MR, mannose receptor; TREM, triggering receptor expressed on myeloid cells.
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