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PIM2 Induced COX-2 and MMP-9 expression in macrophages requires PI3K and Notch1 signaling.

Bansal K, Kapoor N, Narayana Y, Puzo G, Gilleron M, Balaji KN - PLoS ONE (2009)

Bottom Line: PIM2 triggered significant p65 nuclear factor -kappaB (NF-kappaB) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling.Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of Suppressor of Hairless (CSL) and NF-kappaB to respective promoters.Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.

ABSTRACT
Activation of inflammatory immune responses during granuloma formation by the host upon infection of mycobacteria is one of the crucial steps that is often associated with tissue remodeling and breakdown of the extracellular matrix. In these complex processes, cyclooxygenase-2 (COX-2) plays a major role in chronic inflammation and matrix metalloproteinase-9 (MMP-9) significantly in tissue remodeling. In this study, we investigated the molecular mechanisms underlying Phosphatidyl-myo-inositol dimannosides (PIM2), an integral component of the mycobacterial envelope, triggered COX-2 and MMP-9 expression in macrophages. PIM2 triggers the activation of Phosphoinositide-3 Kinase (PI3K) and Notch1 signaling leading to COX-2 and MMP-9 expression in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Notch1 signaling perturbations data demonstrate the involvement of the cross-talk with members of PI3K and Mitogen activated protein kinase pathway. Enforced expression of the cleaved Notch1 in macrophages induces the expression of COX-2 and MMP-9. PIM2 triggered significant p65 nuclear factor -kappaB (NF-kappaB) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling. Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of Suppressor of Hairless (CSL) and NF-kappaB to respective promoters. Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression. Taken together, these data implicate PI3K and Notch1 signaling as obligatory early proximal signaling events during PIM2 induced COX-2 and MMP-9 expression in macrophages.

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Related in: MedlinePlus

Soluble Jagged 1 significantly inhibits PIM2 triggered cleaved Notch1 (NICD), COX-2 or MMP-9 expression.(A). Cleaved Notch1 levels were assessed in RAW 264.7 macrophages transfected either with soluble Jagged1 construct or Vector construct followed by treatment with PIM2. (B). As described in (A), in soluble Jagged1 construct transfected cells, transcript levels of COX-2 were analyzed by quantitative real-time PCR and (C). surface expression of MMP-9 by flow cytometry. The results presented are representative of three independent experiments. Med, Medium.
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pone-0004911-g004: Soluble Jagged 1 significantly inhibits PIM2 triggered cleaved Notch1 (NICD), COX-2 or MMP-9 expression.(A). Cleaved Notch1 levels were assessed in RAW 264.7 macrophages transfected either with soluble Jagged1 construct or Vector construct followed by treatment with PIM2. (B). As described in (A), in soluble Jagged1 construct transfected cells, transcript levels of COX-2 were analyzed by quantitative real-time PCR and (C). surface expression of MMP-9 by flow cytometry. The results presented are representative of three independent experiments. Med, Medium.

Mentions: Further, in addition to siRNA and pharmacological inhibition of Notch1 signaling, we have made use of soluble form of Jagged1, a known Notch1 ligand, to inhibit PIM2 triggered Notch1 signaling. Many studies have reported that, when expressed, extracellular soluble form of Jagged1 exerts dominant-negative effect on Notch signaling possibly by sequestering the Notch receptor and preventing Notch interaction with its ligands [40]–[42]. In this perspective, soluble Jagged1 markedly reduced not only PIM2 triggered cleaved Notch1 (NICD) formation (Figure 4A), but also the subsequent expression of COX-2 and MMP-9 in macrophages (Figure 4B–C).


PIM2 Induced COX-2 and MMP-9 expression in macrophages requires PI3K and Notch1 signaling.

Bansal K, Kapoor N, Narayana Y, Puzo G, Gilleron M, Balaji KN - PLoS ONE (2009)

Soluble Jagged 1 significantly inhibits PIM2 triggered cleaved Notch1 (NICD), COX-2 or MMP-9 expression.(A). Cleaved Notch1 levels were assessed in RAW 264.7 macrophages transfected either with soluble Jagged1 construct or Vector construct followed by treatment with PIM2. (B). As described in (A), in soluble Jagged1 construct transfected cells, transcript levels of COX-2 were analyzed by quantitative real-time PCR and (C). surface expression of MMP-9 by flow cytometry. The results presented are representative of three independent experiments. Med, Medium.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654112&req=5

pone-0004911-g004: Soluble Jagged 1 significantly inhibits PIM2 triggered cleaved Notch1 (NICD), COX-2 or MMP-9 expression.(A). Cleaved Notch1 levels were assessed in RAW 264.7 macrophages transfected either with soluble Jagged1 construct or Vector construct followed by treatment with PIM2. (B). As described in (A), in soluble Jagged1 construct transfected cells, transcript levels of COX-2 were analyzed by quantitative real-time PCR and (C). surface expression of MMP-9 by flow cytometry. The results presented are representative of three independent experiments. Med, Medium.
Mentions: Further, in addition to siRNA and pharmacological inhibition of Notch1 signaling, we have made use of soluble form of Jagged1, a known Notch1 ligand, to inhibit PIM2 triggered Notch1 signaling. Many studies have reported that, when expressed, extracellular soluble form of Jagged1 exerts dominant-negative effect on Notch signaling possibly by sequestering the Notch receptor and preventing Notch interaction with its ligands [40]–[42]. In this perspective, soluble Jagged1 markedly reduced not only PIM2 triggered cleaved Notch1 (NICD) formation (Figure 4A), but also the subsequent expression of COX-2 and MMP-9 in macrophages (Figure 4B–C).

Bottom Line: PIM2 triggered significant p65 nuclear factor -kappaB (NF-kappaB) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling.Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of Suppressor of Hairless (CSL) and NF-kappaB to respective promoters.Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.

ABSTRACT
Activation of inflammatory immune responses during granuloma formation by the host upon infection of mycobacteria is one of the crucial steps that is often associated with tissue remodeling and breakdown of the extracellular matrix. In these complex processes, cyclooxygenase-2 (COX-2) plays a major role in chronic inflammation and matrix metalloproteinase-9 (MMP-9) significantly in tissue remodeling. In this study, we investigated the molecular mechanisms underlying Phosphatidyl-myo-inositol dimannosides (PIM2), an integral component of the mycobacterial envelope, triggered COX-2 and MMP-9 expression in macrophages. PIM2 triggers the activation of Phosphoinositide-3 Kinase (PI3K) and Notch1 signaling leading to COX-2 and MMP-9 expression in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Notch1 signaling perturbations data demonstrate the involvement of the cross-talk with members of PI3K and Mitogen activated protein kinase pathway. Enforced expression of the cleaved Notch1 in macrophages induces the expression of COX-2 and MMP-9. PIM2 triggered significant p65 nuclear factor -kappaB (NF-kappaB) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling. Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of Suppressor of Hairless (CSL) and NF-kappaB to respective promoters. Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression. Taken together, these data implicate PI3K and Notch1 signaling as obligatory early proximal signaling events during PIM2 induced COX-2 and MMP-9 expression in macrophages.

Show MeSH
Related in: MedlinePlus