Peptidoglycan Enhances IL-6 Production in Human Synovial Fibroblasts via TLR2 Receptor, Focal Adhesion Kinase, Akt, and AP-1- Dependent Pathway

Chiu, Yung-Cheng; Lin, Ching‐Yuang; Chen, Chao-Ping; Huang, Kui-Chou; Tong, Kwok-Man; Tzeng, Chung‐Yuh; Lee, Tu-Sheng; Hsu, Horng‐Chaung; Tang, Chih-Hsin

doi:10.4049/jimmunol.0802826

Cited by 91 publications

(93 citation statements)

References 39 publications

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“…It was surprising that activation of the PI3K pathway by LVS infection was TLR2-independent; LVS activates the innate immune response largely through TLR2, and TLR2 ligands have been reported to stimulate PI3K activation (93)(94)(95). Activation of this pathway, however, was completely MyD88-dependent, which suggests that LVS may also signal host cells via a TLR other than TLR2, although neither TLR3, TLR4, nor TLR9 appear to be required based on our results.…”

Section: Discussioncontrasting

confidence: 52%

Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response toFrancisella tularensisLive Vaccine Strain

Medina

Morris

Berton

2010

The Journal of Immunology

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We sought to clarify the role of the PI3‐kinase/Akt pathway in regulating early (< 9 h) proinflammatory responses in macrophages infected with Francisella tularensis Live Vaccine Strain (LVS). LVS‐induced TNF‐α and IL‐6 secretion was markedly increased in macrophages from wildtype C57BL/6 mice pre‐exposed to the PI3‐kinase inhibitor wortmannin compared with vehicle pre‐exposed macrophages; the levels of phosphorylated p38 MAPK and ERK1/2 were also enhanced and remained elevated for a longer period of time. LVS infection rapidly induced MAPK phosphatase‐1 (MKP‐1) expression in a TLR2‐ and PI3‐kinase‐dependent manner. Peak levels of MKP‐1 correlated closely with the decline in p38 MAPK and ERK1/2 phosphorylation. MAPK activation and cytokine production were entirely TLR2‐dependent. Surprisingly, PI3‐kinase/Akt activation was TLR2‐independent; it was also TLR4‐, TLR9‐, TIRAP/Mal‐ and TRIF‐independent. PI3‐kinase activation was, however, dependent on MyD88. These data suggest that LVS infection restrains the TLR2‐triggered pro‐inflammatory response of macrophages via parallel activation of the PI3‐kinase pathway, which enhances MKP‐1 expression. This results in the accelerated deactivation of MAPKs and suppression of proinflammatory cytokine production. This inhibitory pathway may be activated by a novel MyD88‐dependent pattern recognition receptor that is engaged by LVS. This work was supported by NIH grant AI057986.

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Section: Discussioncontrasting

confidence: 52%

Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response toFrancisella tularensisLive Vaccine Strain

Medina

Morris

Berton

2010

The Journal of Immunology

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“…Whether the recruitment of NODs to the plasma membrane is induced by TLR2 activation will be shown in the future. (iii) There are various membrane transporters described in epithelial cells, e.g., hPepT1 and SCL15A4; the latter is thought to be an endosomal oligopeptide transporter that transports bacterial peptides such as N-formylmethionylleucylphenylalanine (fMLP) as well as the NOD agonists MDP and L-Ala-D-Glu-meso-diaminopimelic acid (tri-DAP) (93,94). As hPepT1 expression was upregulated during inflammation triggered by proinflammatory mediators (such as IL-1␤, IL-2, IL-6, IL-8, IL-15, gamma interferon [IFN-␥], TNF-␣, and many more) one should expect that activation of the TLR2-MyD88 pathway should also lead to hPepT1 upregulation and consequently to an increased uptake of NOD agonists.…”

Section: Peptidoglycan (Nod2 Ligand) Acts Synergistically With Tlr2 Lmentioning

confidence: 99%

Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence

Nguyen

Götz

2016

Microbiol Mol Biol Rev

154

170

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SUMMARYSince the discovery in 1973 of the first of the bacterial lipoproteins (Lpp) inEscherichia coli, Braun's lipoprotein, the ever-increasing number of publications indicates the importance of these proteins. Bacterial Lpp belong to the class of lipid-anchored proteins that in Gram-negative bacteria are anchored in both the cytoplasmic and outer membranes and in Gram-positive bacteria are anchored only in the cytoplasmic membrane. In contrast to the case for Gram-negative bacteria, in Gram-positive bacteria lipoprotein maturation and processing are not vital. Physiologically, Lpp play an important role in nutrient and ion acquisition, allowing particularly pathogenic species to better survive in the host. Bacterial Lpp are recognized by Toll-like receptor 2 (TLR2) of the innate immune system. The important role of Lpp in Gram-positive bacteria, particularly in the phylumFirmicutes, as key players in the immune response and pathogenicity has emerged only in recent years. In this review, we address the role of Lpp in signaling and modulating the immune response, in inflammation, and in pathogenicity. We also address the potential of Lpp as promising vaccine candidates.

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“…Cellular lysates were prepared as described Chiu et al, 2009]. Proteins were resolved using SDS-PAGE and transferred to immobilon polyvinyldifluoride membranes.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…After incubation, the medium was removed and stored at À808C until the assay was performed. IL-6 in the medium was assayed using IL-6 enzyme immunoassay kits, according to the procedure described by the manufacturer Chiu et al, 2009].…”

Section: Cell Culturesmentioning

confidence: 99%

Stromal cell‐derived factor‐1/CXCR4 promotes IL‐6 production in human synovial fibroblasts

Chen

Tsou

Hsu

et al. 2011

J of Cellular Biochemistry

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The production of chemokine stromal cell-derived factor (SDF)-1 is significantly higher in synovial fluid of patients with osteoarthritis (OA). IL-6 is a multifunctional cytokine that plays a central role in both OA and rheumatoid arthritis. However, the effects of SDF-1α on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in SDF-1α-induced IL-6 production in human synovial fibroblast cells. SDF-1α caused concentration- and time-dependent increases in IL-6 production. SDF-1α also increased the mRNA and surface expression of CXCR4 receptor in human synovial fibroblasts. CXCR4-neutralizing antibody, CXCR4-specific inhibitor (AMD3100), or small interfering RNA against CXCR4 inhibited the SDF-1α-induced increase of IL-6 expression. The transcriptional regulation of IL-6 by SDF-1α was mediated by phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt and activation of the activator protein (AP)-1 component of c-Jun. The binding of c-Jun to the AP-1 element on the IL-6 promoter and the increase in AP-1 luciferase activity was enhanced by SDF-1α. Co-transfection with CXCR4, PI3K, Akt, and c-Jun mutants or siRNA inhibited the potentiating action of SDF-1α on AP-1 promoter activity. Taken together, our results suggest that SDF-1α-increased IL-6 production in human synovial fibroblasts via the CXCR4 receptor, PI3K, Akt, c-Jun, and AP-1 signaling pathways.

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Peptidoglycan Enhances IL-6 Production in Human Synovial Fibroblasts via TLR2 Receptor, Focal Adhesion Kinase, Akt, and AP-1- Dependent Pathway

Cited by 91 publications

References 39 publications

Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response toFrancisella tularensisLive Vaccine Strain

Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response toFrancisella tularensisLive Vaccine Strain

Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence

Stromal cell‐derived factor‐1/CXCR4 promotes IL‐6 production in human synovial fibroblasts

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