Increased cAMP Levels Modulate Transforming Growth Factor-β/Smad-induced Expression of Extracellular Matrix Components and Other Key Fibroblast Effector Functions

Schiller, Meinhard; Dennler, Sylviane; Anderegg, Ulf; Kokot, Agatha; Simon, Jan C.; Luger, Thomas A.; Mauviel, Alain; Böhm, Markus

doi:10.1074/jbc.m109.038620

Cited by 76 publications

(80 citation statements)

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“…In addition, signaling from CGRP may affect the Smad pathway because the Smad pathway is also an important signaling cascade of TGFβ1. However, Schiller et al 18) reported that intracellular cAMP did not affect phosphorylation and nuclear translocation of Smads. Thus, it is unlikely that cAMP/PKA signals from CGRP are involved in the Smad pathway.…”

Section: Discussionmentioning

confidence: 99%

“…16) Activation of the receptor produces cAMP, a key messenger for various hormones and neuropeptides; the down-stream target of cAMP in neuroblastoma cells is protein kinase A (PKA). 17) Schiller et al 18) have shown that cAMP strongly inhibited expression of TGFβ1-responsive genes. Moreover, cAMP/PKA signals downregulated MAPK pathway in hepatoma, 11) myoblast, 19) and ovary cells.…”

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confidence: 99%

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Calcitonin gene-related peptide regulates mitogen-activated protein kinase pathway to decrease transforming growth factor β1-induced hepatic plasminogen activator inhibitor-1 mRNA expression in HepG2 cells

Matsui

Yamane

Kobayashi‐Hattori

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Calcitonin gene-related peptide regulates mitogen-activated protein kinase pathway to decrease transforming growth factor β1-induced hepatic plasminogen activator inhibitor-1 mRNA expression in HepG2 cells

Matsui

Yamane

Kobayashi‐Hattori

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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“…Another group recently reported that PGD 2 can activate a transcription factor cAMP response element binding protein (CREB) via signaling through extracellular signal-regulated kinase (ERK) and p90 ribosomal S6 protein kinase 1 (RSK1) (28). The cAMP-CREB cascade has been known to antagonize the anabolic effects of TGF-β on ECM deposition (29). Thus these signal pathways might be involved in PGD 2 /DP-mediated anti-fibrotic responses.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin D2 Inhibits Collagen Secretion From Lung Fibroblasts by Activating the DP Receptor

et al. 2013

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Abstract. Lung fibroblasts are responsible for collagen secretion during normal tissue repair and the development of fibrosis. Many other prostaglandins have been reported to regulate collagen synthesis in lung fibroblasts, but the role of prostaglandin D 2 (PGD 2 ) is unknown. In this study, we investigated the effect of PGD 2 on type I collagen secretion in human lung fibroblasts. Pretreatment with PGD 2 (0.1 -10 μM, 1 h) significantly attenuated type I collagen secretion to the cell supernatant induced by transforming growth factor-β (TGF-β). Although an agonist on chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) did not have any effect, the prostanoid DP-receptor agonist BW245C (0.01 -1 μM) suppressed TGF-β-induced collagen secretion. PGD 2 and BW245C significantly increased intracellular cAMP level. One-hour pretreatment with forskolin (0.1 -10 μM), dibutyryl-cAMP (0.01 -1 mM), and the protein kinase A (PKA)-activator N 6 -phenyl-cyclic AMP (100 μM) significantly reduced TGF-β-induced collagen secretion, while exchange protein activated by cAMP (Epac) activator 8-bromo-2′-Omethyladenosine-3′,5′-cyclic AMP (10 μM) did not affect collagen deposition. These results suggest that PGD 2 inhibits TGF-β-induced collagen secretion via intracellular cAMP accumulation through activating DP receptor.

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“…It has been demonstrated that cAMP is a key messenger of many hormones and neuropeptides, some of which modulate the composition of extracellular matrix, and, recently, cAMP/PKA signaling was hypothesized to be involved in the proliferation and activation of rat HSCs (50)(51)(52)(53). The action of cAMP in eukaryotic cells was thought to occur mainly via activation of PKA, and this molecule mediates changes in protein expression and function (36,37).…”

Section: Discussionmentioning

confidence: 99%

The Effector Protein BPE005 from Brucella abortus Induces Collagen Deposition and Matrix Metalloproteinase 9 Downmodulation via Transforming Growth Factor β1 in Hepatic Stellate Cells

et al. 2016

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The liver is frequently affected in patients with active brucellosis. In the present study, we identified a virulence factor involved in the modulation of hepatic stellate cell function and consequent fibrosis during Brucella abortus infection. This study assessed the role of BPE005 protein from B. abortus in the fibrotic phenotype induced on hepatic stellate cells during B. abortus infection in vitro and in vivo. We demonstrated that the fibrotic phenotype induced by B. abortus on hepatic stellate (LX-2) cells was dependent on BPE005, a protein associated with the type IV secretion system (T4SS) VirB from B. abortus. Our results indicated that B. abortus inhibits matrix metalloproteinase 9 (MMP-9) secretion through the activity of the BPE005-secreted protein and induces concomitant collagen deposition by LX-2 cells. BPE005 is a small protein containing a cyclic nucleotide monophosphate binding domain (cNMP) that modulates the LX-2 cell phenotype through a mechanism that is dependent on the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway. Altogether, these results indicate that B. abortus tilts LX-2 cells to a profibrogenic phenotype employing a functional T4SS and the secreted BPE005 protein through a mechanism that involves the cAMP and PKA signaling pathway. Brucellosis is a worldwide zoonosis characterized by hepatomegaly, splenomegaly, and peripheral lymphadenopathy. It is a chronic and debilitating infection caused by Gram-negative facultative intracellular bacteria that infect domestic and wild animals and that can be transmitted to humans (1, 2). The frequency of liver involvement in active brucellosis ranges from 5% to 52% or more (1). However, although numerous studies have focused on brucellar liver histopathology (1), the pathogenic mechanisms of liver disease caused by Brucella have not been completely investigated at the molecular and cellular levels.Liver fibrosis is a wound-healing response to chronic hepatic injury, which may be caused by alcohol abuse, hepatitis virus infection, or nonalcoholic steatohepatitis, and it is characterized by an excessive accumulation of extracellular matrix proteins in the liver (3, 4). An early event in the development of liver fibrosis is the activation of hepatic stellate cells (HSCs), the major cell type responsible for increased synthesis of extracellular matrix proteins (5). An elevated level of transforming growth factor ␤1 (TGF-␤1) is also observed in the damaged liver, and it has a close correlation with fibrogenic changes in HSCs and liver tissue (6-8). In addition, decreased matrix metalloproteinase 9 (MMP-9) expression was observed in alcoholic liver fibrosis (9). This fibrogenic phenotype involves alterations in the balance of MMPs and their natural inhibitors-tissue inhibitors of metalloproteinases (TIMPs). In particular, MMP-2 and MMP-9 (gelatinase A and B, respectively) are important in regulating fibrogenesis and scar degradation. They can degrade a variety of collagens, including basement membrane (type IV collagen), denatured fibrillar...

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Increased cAMP Levels Modulate Transforming Growth Factor-β/Smad-induced Expression of Extracellular Matrix Components and Other Key Fibroblast Effector Functions

Cited by 76 publications

References 78 publications

Calcitonin gene-related peptide regulates mitogen-activated protein kinase pathway to decrease transforming growth factor β1-induced hepatic plasminogen activator inhibitor-1 mRNA expression in HepG2 cells

Calcitonin gene-related peptide regulates mitogen-activated protein kinase pathway to decrease transforming growth factor β1-induced hepatic plasminogen activator inhibitor-1 mRNA expression in HepG2 cells

Prostaglandin D2 Inhibits Collagen Secretion From Lung Fibroblasts by Activating the DP Receptor

The Effector Protein BPE005 from Brucella abortus Induces Collagen Deposition and Matrix Metalloproteinase 9 Downmodulation via Transforming Growth Factor β1 in Hepatic Stellate Cells

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