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.

Recombinant MPT83 Derived fromMycobacterium tuberculosisInduces Cytokine Production and Upregulates the Function of Mouse Macrophages through TLR2

“…The protein moiety of lipoproteins is critical for interaction with TLR2. Immunoprecipitation was used to demonstrate the binding of rMPT83 and TLR2 in the absence of acylation or glycosylation, consistent with previous results showing that the recombinant mycobacterial proteins ESAT6, PPE18, and MPB83 bind to TLR2 (25,65,66). The current findings also are consistent with observations that other LprG and LprA lipoproteins trigger the TLR2-signaling pathway, resulting in the secretion of proinflammatory cytokines, such as TNF-a.…”

Pulmonary Mycobacterial Granuloma

“…11,12,[53][54][55][56][57] M. bovis BCG also uss similar immune evasion strategies as M.tb to dampen host immune activation mechanisms including intracellular persistence, 58 -60 inhibiting MHC molecule expression, 42,61 and inducing IL-10 production. [37][38][39]62 Despite these described similarities, we must caution that, compared with Immunosuppression of Bacterial Granuloma 1631 AJP April 2011, Vol. 178, No.…”

“…65 In a fashion similar to that of the tumor, although it is believed that mycobacteria may simultaneously use multiple mechanisms of immune evasion including mechanisms of down-regulating antigen presentation, 42,61 in the current study we have shown that IL-10 is one of the essential mechanisms through which the immune suppressive environment of mycobacterial granuloma is maintained. Despite the overwhelming evidence to support a direct role of mycobacterial infection in inducing IL-10 production by APCs, [37][38][39]62 it is plausible for us to consider the possibility that some level of IL-10 may be actively induced as part of host immune regulatory mechanisms as a means to limit immunopathology, a concession that could be exploited by mycobacteria and has recently been suggested by others. 66 Although our current findings and a large body of literature information support the immune suppressive role of IL-10 in mycobacterial infection, one study shows the addition of exogenous IL-10 to enhance macrophage activation.…”

“…Evidence in the literature suggests that mycobacterial infection can induce the production of IL-10, [37][38][39] which is a critical immune regulatory cytokine. We thus examined whether granuloma cells produced the immune regulatory cytokine IL-10 and compared its level with that by airway luminal cells.…”

Structure and dynamic behavior of Toll‐like receptor 2 subfamily triggered by malarial glycosylphosphatidylinositols of Plasmodium falciparum

“…The TLR2 subfamily binds with a wide‐range of microbial compounds and proteins in addition to lipoproteins and lipopeptides 25. Among them, peptidoglycan of Staphylococcus aureus can bind to the N ‐terminus or C ‐terminus of the TLR2 42; proline‐proline‐glutamic acid 18 of Mycobacterium tuberculosis has been shown to interact with the C ‐terminal region of TLR2 43; and both the N ‐ and C ‐terminus LRRs of TLR1 and TLR6 play a minimal role in accommodating LT‐IIb‐B 5 44. Hence, we hypothesize that the N ‐ and C ‐terminal fluctuations observed in our analysis are reasonable because they are involved in diverse interactions with multiple ligands.…”