Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine the regulation of type IV collagenase expression in murine peritoneal macrophages (PEM) after they are incubated with LPS. LPS stimulated the production of the latent forms of 92-kDa (MMP-9) and 72-kDa (MMP-2) type IV gelatinases in a dose-dependent (> 10 ng/ml) and serum-dependent manner. Time course analyses revealed that LPS regulated the expression of MMP-9 and MMP-2 via discordant kinetics. Prolonged treatment of PEM with LPS decreased MMP-9 but not MMP-2 activities. IFN-gamma decreased the production of both gelatinases by PEM responding to LPS. TGF-beta stimulated production of both matrix metalloproteinases but blocked the LPS-mediated secretion of MMP-9. LPS-stimulated MMP-9 production was suppressed by genistein and tyrphostin, two specific tyrosine kinase inhibitors, as well as H-7, a serine/threonine protein kinase inhibitor, but not by HA1004, a relatively selective inhibitor for PKA and PKG. Our data demonstrate that the secretion of MMP-2 and MMP-9 by murine PEM is differentially regulated, suggesting a distinct in vivo role for these two otherwise analogous type IV gelatinases in macrophage-mediated connective tissue destruction at sites of immunologic challenges.
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PMID:Regulatory mechanisms for the expression of type IV collagenases/gelatinases in murine macrophages. 814 39

We recently demonstrated that different CD45 monoclonal antibodies (mAb) are able to induce cellular aggregation in human peripheral blood mononuclear cells (PBMC) through LFA-1/ICAM-1 interactions. Such interactions could be down-modulated by protein kinase (PK) A/G inhibitors, but were unaffected by inhibitors of PKC, suggesting the involvement of PKA or PKG in CD45 mAb-induced adhesion. In this study we show that after incubation of PBMC with several (but not all) mAb to CD45, CD45RO and CD45RA, intracellular cAMP, but not cGMP concentrations readily increase, reaching a maximum 30 min after start of activation. As evidenced by several lines of investigation cAMP accumulation was independent of Fc receptor-associated signaling as well as tyrosine phosphatase activity of CD45. In highly pure T lymphocytes, CD45 mAb were unable to induce cAMP synthesis, but readily did so after addition of autologous monocytes. After paraformaldehyde fixation of both quiescent or IFN-gamma/TNF-alpha-preactivated monocytes, cAMP production was no longer detectable, suggesting monocytes as the cell of origin for the increased cAMP synthesis. Further, cAMP accumulation in monocytes occurred after reconstitution to T lymphocytes preincubated with CD45 mAb and extensively washed. Importantly, pretreatment of T lymphocyte/monocyte mixtures with LFA-1 mAb and/or ICAM-1 mAb down-regulated CD45 mAb-induced cAMP synthesis. Finally, we demonstrate that CD45 mAb are not only capable of inducing cAMP production, but also of directly stimulating PKA enzyme activity. Based on the data presented, we propose that CD45 signaling in T lymphocytes subsequently activates cAMP accumulation and PKA activation in monocytes via LFA-1/ICAM-1-dependent cellular interactions.
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PMID:Epitope-specific signaling through CD45 on T lymphocytes leads to cAMP synthesis in monocytes after ICAM-1-dependent cellular interaction. 971 Feb 8

Catecholamines can suppress production of inflammatory mediators in different cell types, including airway epithelium, but downstream signaling mechanisms involved in regulation of these antiinflammatory effects are largely unknown. We theorized that acute beta2-adrenergic stimulation of airway epithelial cells with albuterol could suppress the production and release of inflammatory mediators, specifically granulocyte macrophage-colony stimulating factor (GM-CSF) via a pathway involving inducible nitric oxide synthase (iNOS). Normal human bronchial epithelial (NHBE) cells in primary culture were exposed to a cytokine mixture (10 ng/ml each IFN-gamma and IL-1beta) to induce iNOS expression. (R)- and (S)-enantiomers of albuterol, as well as racemic mixtures, were added with these cytokines, and effects on GM-CSF expression and production were assessed. Specific inhibitors and activators of protein kinases (PKs), beta2-adrenergic receptor antagonists, and small interfering RNAs against iNOS were used to delineate signaling pathways involved. iNOS message was significantly upregulated in a concentration-dependent manner by the active (R)-enantiomer of albuterol. (R)-albuterol also attenuated cytokine-induced increases in GM-CSF steady-state mRNA expression and protein release. The (S)-enantomer of albuterol had no effect on these parameters. PKC, specifically, the delta isoform, was required for iNOS message increase, but PKA and PKG were not involved in the pathway. Overall, this study identifies a novel pathway by which beta2-adrenergic agonists may exhibit antiinflammatory effects in airway epithelium and surrounding milieu.
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PMID:(R)-albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS. 1619 34

The activity of an inwardly rectifying K(+) channel in cultured human renal proximal tubule cells (RPTECs) is stimulated and inhibited by nitric oxide (NO) at low and high concentrations, respectively. In this study, we investigated the effects of IFN-gamma, one of the cytokines which affect the expression of inducible NO synthase (iNOS), on intracellular NO and channel activity of RPTECs, using RT-PCR, NO imaging, and the cell-attached mode of the patch-clamp technique. Prolonged incubation (24 h) of cells with IFN-gamma (20 ng/ml) enhanced iNOS mRNA expression and NO production. In these cells, a NOS inhibitor, N(omega)-nitro-l-arginine methyl ester (l-NAME; 100 microM), elevated channel activity, suggesting that NO production was so high as to suppress the channel. This indicated that IFN-gamma would chronically suppress channel activity by enhancing NO production. Acute effects of IFN-gamma was also examined in control cells. Simple addition of IFN-gamma (20 ng/ml) to the bath acutely stimulated channel activity, which was abolished by inhibitors of IFN-gamma receptor-associated Janus-activated kinase [P6 (1 microM) and AG490 (10 microM)]. However, l-NAME did not block the acute effect of IFN-gamma. Indeed, IFN-gamma did not acutely affect NO production. Moreover, the acute effect was not blocked by inhibition of PKA, PKG, and phosphatidylinositol 3-kinase (PI3K). We conclude that IFN-gamma exerted a delayed suppressive effect on K(+) channel activity by enhancing iNOS expression and an acute stimulatory effect, which was independent of either NO pathways or phosphorylation processes mediated by PKA, PKG, and PI3K in RPTECs.
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PMID:Delayed and acute effects of interferon-gamma on activity of an inwardly rectifying K+ channel in cultured human proximal tubule cells. 1894 31