The PPE18 of Mycobacterium tuberculosis interacts with TLR2 and activates IL-10 induction in macrophage.
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.
Nair
Shiny
S
Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad, India.
Ramaswamy
Poongothai A
PA
Ghosh
Sudip
S
Joshi
Dhananjay C
DC
Pathak
Niteen
N
Siddiqui
Imran
I
Sharma
Pawan
P
Hasnain
Seyed E
SE
Mande
Shekhar C
SC
Mukhopadhyay
Sangita
S
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
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