Recombinant MPT83 Derived from<i>Mycobacterium tuberculosis</i>Induces Cytokine Production and Upregulates the Function of Mouse Macrophages through TLR2

Chen, Suting; Li, Jiayun; Zhang, Yi; Gao, Xiang; Cai, Hong

doi:10.4049/jimmunol.1102177

Cited by 48 publications

(43 citation statements)

References 76 publications

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“…MTB lipoproteins have either stimulatory or inhibitory effects on host antigen presenting cells (APCs), some of which are TLR2 dependent (Harding and Boom, 2010). Lipoprotein MPT83, a TLR2 ligand, promoted IFN-γ-induced MHC II expression and enhanced the ability of macrophages to present the MPT83 peptide to CD4 + T by (Chen et al, 2012). However, prolonged exposure to other lipoproteins such as Lpr A, Lpr G as well as 19-kDa lipoproteins inhibited IFN-γ-induced MHC-II expression and antigen presentation via TLR2 (Pecora et al, 2006; Drage et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Zhu

et al. 2016

Front. Cell. Infect. Microbiol.

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TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (MTB) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized MTB lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2−/− mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular MTB to evade immune surveillance and maintain chronic infection.

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Section: Introductionmentioning

confidence: 99%

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Zhu

et al. 2016

Front. Cell. Infect. Microbiol.

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“…Splenic lymphocytes were isolated and cultured as previously described. 13 Ag processing and presentation RAW264.7 cells (2.5310 4 cells/well) were incubated in 96-well plates with rBCSP31 (0 or 5 mg/ml) and IFN-c (0 or 20 ng/ml) for 36 h at 37 uC. After replacing the medium, the cells were incubated with rBCSP31 (5 mg/ml) for 2 h to elicit Ag presentation.…”

Section: Isolation Of Splenic Lymphocytesmentioning

confidence: 99%

“…Cells were aseptically isolated and cultured as previously described. 13 Non-adherent cells were removed by washing twice with medium and then were treated with rBCSP31 (5 mg/ml), LPS (1 mg/ml) or peptidoglycans (PGNs; 10 mg/ml).…”

Section: Rt-pcr and Quantitative Rt-pcr (Qrt-pcr)mentioning

confidence: 99%

“…TLR2 and TLR4 are mainly required for signaling initiated by multiple ligands from Gram-negative and -positive bacteria, mycobacteria, spirochetes and mycoplasmas, such as lipoteichoic acid, peptidoglycans, lipoproteins and certain types of lipopolysaccharide (LPS). [8][9][10][11][12][13][14][15][16] Most TLRs use myeloid differentiation factor 88 (MyD88) with the exception of TLR3, which exclusively recruits Toll-IL-1 resistance domain-containing adaptor-inducing IFN-b (TRIF). 17 TLR4 is the only member of the TLR family that exploits both MyD88 and TRIF to induce the downstream targets of the signaling cascade.…”

Section: Introductionmentioning

confidence: 99%

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TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

Yuan

Gao

et al. 2014

Cell Mol Immunol

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Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors (TLRs) recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 (rBCSP31) to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-a, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases (MAPKs) by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-kB in macrophages. In addition, continuous exposure (.24 h) of RAW264.7 cells to rBCSP31 significantly enhanced IFN-c-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4 1 T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2 2/2 and TLR4 2/2 mice was lower than that from C57BL/6 macrophages, and the activation of NF-kB and MAPKs was attenuated in macrophages from TLR2 2/2 and TLR4 2/2 mice. In addition, CD4 1 T cells from C57BL/6 mice immunized with rBCSP31 produced higher levels of IFN-c and IL-2 compared with CD4 1 T cells from TLR2 2/2 and TLR4 2/2 mice. Macrophages from immunized C57BL/6 mice produced higher levels of IL-12p40 than those from TLR2 2/2 and TLR4 2/2 mice. Furthermore, immunization with rBCSP31 provided better protection in C57BL/6 mice than in TLR2 2/2 and TLR4 2/2 mice after B. abortus 2308 challenge. These results indicate that rBCSP31 is a TLR2 and TLR4 agonist that induces cytokine production, upregulates macrophage function and induces the Th1 immune response.

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“…Cells were aseptically isolated and cultured as previously described. 46 Non-adherent cells were removed by washing twice with medium, and then the adherent cells were treated with rLrp (5 mg mL 21 ), LPS (1 mg mL 21 ) (L4391; Sigma-Aldrich), or PGN (10 mg mL 21 ) (69554; Sigma-Aldrich).…”

Section: Measurement Of Cytokine Levelsmentioning

confidence: 99%

The rLrp of Mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2-mediated PI3K/Akt pathway activation-dependent mechanism

Liu

Chen

et al. 2015

Cell Mol Immunol

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We demonstrate that Mycobacterium tuberculosis recombinant leucine-responsive regulatory protein (rLrp) inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α), interleukin-6, and interleukin-12 production and blocks the nuclear translocation of subunits of the nuclear-receptor transcription factor NF-κB (Nuclear factor-kappa B). Moreover, rLrp attenuated LPS-induced DNA binding and NF-κB transcriptional activity, which was accompanied by the degradation of inhibitory IκBα and a consequent decrease in the nuclear translocation of the NF-κB p65 subunit. RLrp interfered with the LPS-induced clustering of TNF receptor-associated factor 6 and with interleukin-1 receptor-associated kinase 1 binding to TAK1. Furthermore, rLrp did not attenuate proinflammatory cytokines or the expression of CD86 and major histocompatibility complex class-II induced by interferon-gamma in the macrophages of Toll-like receptor 2 deletion (TLR2) mice and in protein kinase b (Akt)-depleted mouse cells, indicating that the inhibitory effects of rLrp were dependent on TLR2-mediated activation of the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. RLrp could also activate the PI3K/Akt pathway by stimulating the rapid phosphorylation of PI3K, Akt, and glycogen synthase kinase 3 beta in macrophages. In addition, 19 amino acid residues in the N-terminus of rLrp were determined to be important and required for the inhibitory effects mediated by TLR2. The inhibitory function of these 19 amino acids of rLrp raises the possibility that mimetic inhibitory peptides could be used to restrict innate immune responses in situations in which prolonged TLR signaling has deleterious effects. Our study offers new insight into the inhibitory mechanisms by which the TLR2-mediated PI3K/Akt pathway ensures the transient expression of potent inflammatory mediators.

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

Cited by 48 publications

References 76 publications

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

The rLrp of Mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2-mediated PI3K/Akt pathway activation-dependent mechanism

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