The PPE18 Protein of <i>Mycobacterium tuberculosis</i> Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

Nair, Shiny; Pandey, Akhilesh; Mukhopadhyay, Sangita

doi:10.4049/jimmunol.1000773

Cited by 79 publications

(64 citation statements)

References 85 publications

(123 reference statements)

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“…rMPT83 induces translocation of NF-kB/rel subunits to the nucleus in mouse macrophages NF-kB is an important transcription factor that is involved in the induction of proinflammatory cytokines (49)(50)(51) and the expression of costimulatory molecules. The promoters of IL-12 p40 (52, 53) and TNF-a (51, 54) contain NF-kB binding sites, and transcription of these genes is dependent essentially on the binding of NF-kB/rel transcription factors to the NF-kB binding sites.…”

Section: Rmpt83 Induces Phosphorylation Of Mapks and This Effect Is mentioning

confidence: 99%

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: Rmpt83 Induces Phosphorylation Of Mapks and This Effect Is mentioning

confidence: 99%

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 our earlier studies, we have reported that two members of the PPE family of proteins of M. tuberculosis, PPE17 and PPE18, induced antagonistic inflammatory responses upon interaction with TLR2 (10,11,24). The reasons for such contrasting immune responses emanating from the same TLR2 when engaged to two different proteins are unique.…”

Section: Discussionmentioning

confidence: 99%

“…In our earlier studies, we had shown that the recombinant PPE17 and PPE18 proteins bind to TLR2 at different regions and elicit different signaling cascades (10,11,24). Although PPE17 was found to bind to the leucine-rich repeat (LRR) 16-20 and induced a proinflammatory-type response, PPE18 interacted with the LRR 11-15 and triggered an anti-inflammatory type response.…”

Section: Ppe17 and Ppe18 Cause Differential Dimerization Of Tlr2mentioning

confidence: 99%

“…We had shown earlier that PPE17 predominantly induced the NF-kB and the proinflammatory cytokine TNF-a (11), whereas PPE18 inhibited nuclear NF-kB signaling and activated induction of the anti-inflammatory cytokine IL-10 in macrophages (10,11,24). We therefore looked at molecules involved in regulating this cytokine signaling downstream of TLR2.…”

Section: Ppe17 Causes Translocation Of Irak3 Into the Cytosolmentioning

confidence: 99%

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Transduction of Functionally Contrasting Signals by Two Mycobacterial PPE Proteins Downstream of TLR2 Receptors

Udgata

Qureshi

Mukhopadhyay

2016

The Journal of Immunology

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As pathogen-associated molecular pattern sensors, the TLRs can detect diverse ligands to elicit either proinflammatory or anti-inflammatory responses, but the mechanism that dictates such contrasting immune responses is not well understood. In this work, we demonstrate that proline–proline–glutamic acid (PPE)17 protein of Mycobacterium tuberculosis induces TLR1/2 heterodimerization to elicit proinflammatory-type response, whereas PPE18-induced homodimerization of TLR2 triggers anti-inflammatory type responses. Ligation of TLR1/2 caused an increased recruitment of IL-1R–associated kinase (IRAK)1, MyD88, and protein kinase C (PKC)ε to the downstream TLR-signaling complex that translocated PKCε into the nucleus in an IRAK1-dependent manner. PKCε-mediated phosphorylation allowed the nuclear IRAK3 to be exported to the cytoplasm, leading to increased activation of ERK1/2, stabilization of MAPK phosphatase 1 (MKP-1), and induction of TNF-α with concomitant downregulation of p38MAPK. Silencing of TLR1 inhibited PPE17-triggered cytoplasmic export of IRAK3 as well as TNF-α induction, suggesting an important role of TLR1/2 heterodimer in regulating proinflammatory responses via the IRAK3-signaling pathway. In contrast, PPE18-mediated homodimerization of TLR2 caused poorer cytoplasmic export of nuclear IRAK3 and MKP-1 stabilization, resulting in increased p38MAPK activation. Our study hints to a novel mechanism that implicates PKCε–IRAK3–MKP-1 signaling in the regulation of MAPK activity and inflammatory cascades downstream of TLR2 in tuberculosis.

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“…Although the underlying pathophysiology of sepsis has not been completely elucidated, TNF-α and HMGB1 upregulation is known to play a critical role in the inlammatory response [4][5][6]. Moreover, suppressor of cytokine signaling-3 (SOCS3), a feedback inhibitor of lipopolysaccharide (LPS)-induced inlammation, has been shown to be a key player in inhibiting nuclear factor (NF)-κB-mediated pro-inlammatory cytokine production [7][8][9]. Antiinlammatory strategies have been investigated with favorable efects in animal models of sepsis but with marginal results in humans [10].…”

Section: Introductionmentioning

confidence: 99%

Kallistatin in Sepsis: Protective Actions and Potential Therapeutic Applications

Chao¹,

Li²,

Chao³

2017

Sepsis

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Sepsis is a systemic inlammatory response to infection, leading to multiorgan injury and mortality. Kallistatin is an endogenous protein expressed in the liver and tissues relevant to cardiovascular function. Kallistatin levels are markedly reduced in patients with sepsis and liver disease and in lipopolysaccharide (LPS)-induced septic mice. Kallistatin administration atenuates inlammation, multiorgan damage, and lethality in septic mice with LPS treatment, group A streptococcal, or polymicrobial infection. Importantly, kallistatin treatment not only prevents but also reverses organ injury and lethality in septic mice. Kallistatin decreases sepsis-induced inlammatory responses and tissue damage by modulating diferential signaling pathways, including: (1) stimulating endothelial nitric oxide (eNOS) and sirtuin 1 (SIRT) synthesis, and NO formation; (2) increasing suppressor of cytokine signaling-3 (SOCS3) expression; (3) antagonizing tumor necrosis factor-α (TNF-α) and high mobility group box 1 (HMGB1)-mediated oxidative stress and inlammatory gene expression; and (4) displaying bactericidal efects by stimulating superoxide formation. Therefore, kallistatin's multifactorial activities provide efective protection during septic shock in animal models. As kallistatin displays no apparent cytotoxicity, kallistatin therapy may provide a promising approach for the treatment of sepsis in humans.

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The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

Cited by 79 publications

References 85 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

Transduction of Functionally Contrasting Signals by Two Mycobacterial PPE Proteins Downstream of TLR2 Receptors

Kallistatin in Sepsis: Protective Actions and Potential Therapeutic Applications

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