title: The PPE18 of Mycobacterium tuberculosis interacts with TLR2 and activates IL-10 induction in macrophage.
abstract: The pathophysiological functions of proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins of Mycobacterium tuberculosis are not well understood. In this study, we demonstrate that one of the PPE proteins, PPE18 can stimulate macrophages to secrete IL-10, known to favor a Th2 type response. The recombinant PPE18 was found to specifically interact with the TLR2 leading to an early and sustained activation of p38 MAPK, which is critical for IL-10 induction. In silico docking analyses and mutation experiments indicate that PPE18 specifically interacts with the leucine rich repeat 11 approximately 15 domain of TLR2 and the site of interaction is different from that of a synthetic lipopeptide Pam(3)CSK(4) known to activate predominantly ERK 1/2. When PMA-differentiated THP-1 macrophages were infected with a mutant Mycobacterium tuberculosis strain lacking the PPE18, produced poorer levels of IL-10 as compared with those infected with the wild-type strain. In contrast, an M. smegmatis strain overexpressing the PPE18 induced higher levels of IL-10 in infected macrophages. Our data indicate that the PPE18 protein may trigger an anti-inflammatory response by inducing IL-10 production.
authors.affiliation: Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad, India.
authors.forename: Shiny
authors.initials: S
authors.lastname: Nair
authors.forename: Poongothai A
authors.initials: PA
authors.lastname: Ramaswamy
authors.forename: Sudip
authors.initials: S
authors.lastname: Ghosh
authors.forename: Dhananjay C
authors.initials: DC
authors.lastname: Joshi
authors.forename: Niteen
authors.initials: N
authors.lastname: Pathak
authors.forename: Imran
authors.initials: I
authors.lastname: Siddiqui
authors.forename: Pawan
authors.initials: P
authors.lastname: Sharma
authors.forename: Seyed E
authors.initials: SE
authors.lastname: Hasnain
authors.forename: Shekhar C
authors.initials: SC
authors.lastname: Mande
authors.forename: Sangita
authors.initials: S
authors.lastname: Mukhopadhyay
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000276:immunology* / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C544170:Rv1196 protein, Mycobacterium tuberculosis; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4