Abstract
Treatment of pancreatic acinar cells by hydrogen sulphide has been shown to induce apoptosis. However, a potential role of mitogen-activated protein kinases (MAPKs) in this apoptotic pathway remains unknown. The present study examined the role of MAPKs in H2S-induced apoptosis in mouse pancreatic acinar cells. Pancreatic acinar cells were treated with 10 μM NaHS (a donor of H2S) for 3 hrs. For the evaluation of the role of MAPKs, PD98059, SP600125 and SB203580 were used as MAPKs inhibitors for ERK1/2, JNK1/2 and p38 MAPK, respectively. We observed activation of ERK1/2, JNK1/2 and p38 when pancreatic acini were exposed to H2S. Moreover, H2S-induced ERK1/2, JNK1/2 and p38 activation were blocked by pre-treatment with their corresponding inhibitor in a dose-dependent manner. H2S-induced apoptosis led to an increase in caspase 3 activity and this activity was attenuated when caspase 3 inhibitor were used. Also, the cleavage of caspase 3 correlated with that of poly-(ADP-ribose)-polymerase (PARP) cleavage. H2S treatment induced the release of cytochrome c, smac from mitochondria into the cytoplasm, translocation of Bax into mitochondria and decreased the protein level of Bcl-2. Inhibition of ERK1/2 using PD98059 caused further enhancement of apoptosis as evidenced by annexin V staining, while SP600125 and SB203580 abrogated H2S-induced apoptosis. Taken together, the data suggest that activation of ERKs promotes cell survival, whereas activation of JNKs and p38 MAP kinase leads to H2S-induced apoptosis.
Highlights
Mitogen-activated protein kinases (MAPK) superfamily consist of three family members: the extracellular signal-regulated kinases (ERK), c-jun N-terminal kinase (JNK) and p38 [1]
We examined the activation of ERK1/2, JNK1/2 and p38 kinases in isolated pancreatic acinar cells exposed to H2S
To analyse the consequence of the activation of ERK, JNK and p38 Recent evidence indicates that the MAPK family protein kinases MAP kinase induced by NaHS, we measured annexin V binding, a are important mediators of apoptosis induced by stressful stimuli
Summary
Mitogen-activated protein kinases (MAPK) superfamily consist of three family members: the extracellular signal-regulated kinases (ERK), c-jun N-terminal kinase (JNK) and p38 [1]. ERKs, JNKs and p38 MAP kinase are structurally related, and all of them are activated by phosphorylation of threonine and tyrosine. These play crucial roles in determining whether the cell dies or survives (proliferation or apoptosis) [2]. ERK 1 and 2 are part of the ras/raf/MEK pathway often associated with proliferation and survival [3].ERK-regulating kinase (MEK) has been shown to activate ERKs, but MEK independent activation has been reported [4, 5]. Treatment of pancreatic acinar cells by H2S induces acinar cell apoptosis [16] and it has been reported that H2Sinduced hypoxia triggers the proliferative phases of cell cycle entry in non-transformed rat intestinal epithelial cells [17]. A variety of apoptotic stimuli induce a doi:10.1111/j.1582-4934.2008.00318.x
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