title: Arabinosylated lipoarabinomannan (Ara-LAM) mediated intracellular mechanisms against tuberculosis infection: involvement of protein kinase C (PKC) mediated signaling.
abstract: Tuberculosis causes severe immunosuppression thereby ensuring the loss of the host protective immune responses. During Mycobacterium tuberculosis infection, the pathogen modulates TLR-2 receptor down-stream signaling, indicating the possible involvement of TLR-2 in the regulation of the host immune response. Moreover, different PKC isoforms are also involved in the course of infection. Arabinosylated lipoarabinomannan (Ara-LAM) possesses immuno-modulatory properties which induce the pro-inflammatory responses via induction of TLR-2-mediated signaling. Here, we found that pretreatment of M. tuberculosis-infected macrophages with Ara-LAM caused a significant increase in the conventional PKC expression along with their active association with TLR-2. This association activated the TLR-2 -mediated downstream signaling, facilitating the activation of MAP kinase P38. All these events culminated in the up-regulation of proinflammatory response, which was abrogated by treatment with PKC-α and P38 inhibitors. Moreover, pretreatment of macrophages with Ara-LAM abrogated the IL-10 production while restored MHC-II expression in the infected macrophages. This study demonstrates that Ara-LAM confers protection against tuberculosis via TLR-2/PKC signaling crosstalk which is responsible for the induction of host protective immune response against tuberculosis.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata, India.
authors.forename: Shibali
authors.initials: S
authors.lastname: Das
authors.affiliation: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata, India.
authors.forename: Oindrila
authors.initials: O
authors.lastname: Bhattacharjee
authors.affiliation: Dept. of Microbiology, Institute of Post Graduate Medical Education & Research, Kolkata, India.
authors.forename: Avranil
authors.initials: A
authors.lastname: Goswami
authors.affiliation: Dept. of Microbiology, Institute of Post Graduate Medical Education & Research, Kolkata, India; Dept. of Microbiology, N.R.S Medical College, Kolkata, India.
authors.forename: Nishith K
authors.initials: NK
authors.lastname: Pal
authors.affiliation: Division of Molecular Medicine, Bose Institute, P1/12, C.I.T. Scheme VII-M, Kolkata, India. Electronic address: subrata@bic.boseinst.ernet.in.
authors.forename: Subrata
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001089:Arabinose; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014376:Tuberculosis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000995:Antitubercular Agents; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009573:Nitrites; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C050016:lipoarabinomannan; D001089:Arabinose; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases
keywords: Ara-LAM; Immune modulation; Immune response; Protein kinase C; TLR-2