The<i>Mycobacterium tuberculosis</i>19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Regulated HLA-DR and FcγR1 on Human Macrophages through Toll-Like Receptor 2

Gehring, Adam J.; Rojas, R.M.; Canaday, David H.; Lakey, David; Boom, W. Henry

doi:10.1128/iai.71.8.4487-4497.2003

Cited by 153 publications

(132 citation statements)

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“…In addition to the classical function of MHC-II molecules in presenting Ag to CD4 + T cells, MHC-II molecules can activate various cellular functions in immune or nonimmune cells when cross-linked by Ab or superantigen (75)(76)(77)(78). Previous studies showed that prolonged TLR2 signaling by mycobacterial lipoproteins, such as 19-kDa lipoprotein, inhibits MHC-II expression and Ag processing in macrophages (20,22). In our studies, prolonged TLR2 signaling by rMPT83 enhanced MHC-II expression and Ag presentation by macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…The 19-kDa lipoprotein may block CD4 + T cell activation by decreasing peptide-MHC-II expression and inhibiting the IFN-g-induced chromatin remodeling of MHC2TA. CCAATT/enhancer-binding protein-b and -d are induced by TLR2 signaling and bind to CIITA promoters, which contributes to the inhibition of CIITA and results in decreased MHC-II molecule expression and inhibition of Ag presentation (22,41,80); together, these effects may promote the survival of M. tuberculosis within macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, TLR2 deficiency increases susceptibility to M. tuberculosis infection (15,16). Several mycobacterial ligands for TLR2 have been identified, including lipomannan (17), lipoarabinomannan (18,19), and the lipoproteins LpqH (19 kDa; Rv3763) (20)(21)(22), LprG (Rv1411c) (23), LprA (24), MPB83 (25), and a 38-kDa lipoprotein (26).…”

mentioning

confidence: 99%

“…The survival of M. tuberculosis may be associated with an inhibition of IFNg-dependent responses. Prolonged (.18 h) infection of macrophages with M. tuberculosis or exposure to lipoarabinomannan, 19-kDa lipoprotein, LprG, or LprA inhibits the IFN-g-induced expression of certain genes (20)(21)(22)(23)(24). M. tuberculosis also inhibits macrophage expression of CIITA and genes that are regulated by CIITA, including MHC-II, H2-M, and invariant chain (40).…”

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confidence: 99%

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

Chen

Zhang

et al. 2012

The Journal of Immunology

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TLR2 recognizes components of Mycobacterium tuberculosis and initiates APC activities that influence both innate and adaptive immunity. M. tuberculosis lipoproteins are an important class of TLR2 ligands. In this study, we focused on recombinant MPT83 (rMPT83) to determine its effects on mouse macrophages. We demonstrated that rMPT83 induced the production of TNF-α, IL-6, and IL-12 p40 and that cytokine induction depended on activated MAPKs, because we observed the rapid phosphorylation of ERK1/2, p38, and JNK in macrophages. Additionally, neutralizing Abs against TLR2 significantly inhibited cytokine secretion and reduced or attenuated the rMPT83-induced activation of p38 and JNK in RAW264.7 cells, a mouse macrophage cell line. Furthermore, rMPT83-induced cytokine production was significantly lower in macrophages from TLR2−/− mice than in macrophages from wild-type mice. We further found that prolonged exposure (>24 h) of RAW264.7 cells or macrophages from wild-type and TLR2−/− mice to rMPT83 resulted in a significant enhancement of IFN-γ–induced MHC class II expression and an enhanced ability of macrophages to present the rMPT83 peptide to CD4+ T cells. These results indicated that rMPT83 is a TLR2 agonist that induces the production of cytokines by macrophages and upregulates macrophage function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Chen

Zhang

et al. 2012

The Journal of Immunology

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“…In contrast to the induction of anti-microbial activity by TLR2 stimulation found here and in most reports, some have reported inhibitory effects following triggering of TLR2. TLR2 agonists have been shown to inhibit IFN-c signaling in macrophages [45][46][47]. In addition, the mycobacterial protein ESAT-6 was found to interfere with TLR2 signaling by directly binding to this receptor [48].…”

Section: Discussionmentioning

confidence: 99%

Engagement of Toll‐like receptor 2 in mouse macrophages infected with Mycobacterium avium induces non‐oxidative and TNF‐independent anti‐mycobacterial activity

et al. 2008

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Toll-like receptor (TLR) 2 plays an important role in the immune response to mycobacterial infections, being required for optimal immunity against certain virulent Mycobacterium avium strains. Here we analyzed the role of TLR2 in the intra-macrophagic growth of M. avium, using macrophages from TLR2-deficient mice. We found that the engagement of TLR2/TLR6 and/or TLR2/TLR1 receptors induced bacteriostasis of M. avium inside bone marrow-derived macrophages in a MyD88-dependent way. Additionally, lipoproteins from the cell envelope of M. avium with a molecular mass of 20-25 kDa triggered this TLR2 pathway, leading to a decrease in the growth of the mycobacteria. Although TLR2 engagement induced the production of TNF, this cytokine as well as nitric oxide and superoxide molecules were not necessary for TLR2-mediated bacteriostasis. Finally, TLR ligation did not induce the expression of the 47-kDa guanosine triphosphatase (LRG-47) but it promoted an increased maturation of the phagosome with regards to acquisition of LAMP1. Our data show that triggering TLR2 inhibited M. avium growth by an as-yetunknown mechanism that may involve increased phagosome maturation.Key words: Immunity Á Nitric oxide Á Phagocytes IntroductionMacrophages initiate the innate immune response by recognizing pathogens, phagocytosing them and producing inflammatory mediators. The initiation of an effective response requires the recognition of conserved molecular structures (pathogen associated molecular patterns) found in a large variety of microbes, and recognized by pattern recognition receptors (PRR) that are expressed on myeloid and other cells [1, 2]. The mammalian Tolllike receptors (TLR) are a structurally conserved family that shares homology to the Drosophila Toll system and represent one group of PRR that plays an important role in the recognition of infecting microbes [1][2][3]. Distinct TLR recognize a variety of chemically diverse agonists. These include lipopolysaccharide (LPS), peptidoglycan, viral coat proteins, lipoproteins, glycolipids, dsRNA and CpG DNA [4].TLR are comprised of two major domains: an extracellular leucine-rich repeats (LRR) domain and an intracellular Toll/IL-1 receptor (TIR) domain. The TIR domain, which is present in all TLR, is responsible for initiating a signaling cascade through interactions with TIR-domain-containing adaptors. Most TLR, including TLR2, recruit the MyD88 adaptor molecule, which leads to the activation of nuclear factor (NF)-jB and mitogen-activated protein (MAP) kinases, resulting in the induction of inflammatory cytokines [5,6]. MyD88-and TLR2-deficient mice have been shown to be more susceptible to several microbial infections, including Mycobacterium avium infections [7,8]. However, there are at least three other adaptor proteins, some of which can be used in a TLR-specific way. Thus, this indicates that the signaling pathways through individual TLR may differ from each other and thereby result in different biological responses [9][10][11]. TLR2 recognizes a wide variety of microbial c...

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Mycobacterium tuberculosis: Life and Death in the Phagosome

Russell¹

2008

Handbook of Tuberculosis

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TheMycobacterium tuberculosis19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Regulated HLA-DR and FcγR1 on Human Macrophages through Toll-Like Receptor 2

Cited by 153 publications

References 45 publications

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

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

Engagement of Toll‐like receptor 2 in mouse macrophages infected with Mycobacterium avium induces non‐oxidative and TNF‐independent anti‐mycobacterial activity

Mycobacterium tuberculosis: Life and Death in the Phagosome

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