TY - JOUR
T1 - The PPE18 of Mycobacterium tuberculosis interacts with TLR2 and activates IL-10 induction in macrophage
AU - Nair, Shiny
AU - Ramaswamy, Poongothai A.
AU - Ghosh, Sudip
AU - Joshi, Dhananjay C.
AU - Pathak, Niteen
AU - Siddiqui, Imran
AU - Sharma, Pawan
AU - Hasnain, Seyed E.
AU - Mande, Shekhar C.
AU - Mukhopadhyay, Sangita
PY - 2009/11/15
Y1 - 2009/11/15
N2 - 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 11-15 domain of TLR2 and the site of interaction is different from that of a synthetic lipopeptide Pam3CSK4 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.
AB - 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 11-15 domain of TLR2 and the site of interaction is different from that of a synthetic lipopeptide Pam3CSK4 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.
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U2 - 10.4049/jimmunol.0901367
DO - 10.4049/jimmunol.0901367
M3 - Article
C2 - 19880448
AN - SCOPUS:77954230361
VL - 183
SP - 6269
EP - 6281
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 10
ER -