“…In addition, we have shown previously that miR-29b is anti-fibrotic in CD intestinal fibrosis (Nijhuis et al 2014). This accords well with both our observation here, that this miRNA up-regulates MCL-1L in fibroblasts, and the reported anti-fibrotic properties in the liver (Kahraman et al 2009; Vick et al 2009; Weng et al 2011). Hence, we hypothesised that the up-regulation of MCL-1L via miR-29b in intestinal CD fibroblasts is indirect.…”
Section: Discussionsupporting
confidence: 93%
“…However, these investigations did not identify the MCL-1 isoform directly. Deletion of the Mcl-1 gene in murine hepatocytes resulted in liver cell damage caused by spontaneous induction of apoptosis (Weng et al 2011). Evaluation of MCL-1 in CD intestinal fibrosis and any inter-action with miR-29b, remains to be investigated.Fig.…”
The miR-29 family is involved in fibrosis in multiple organs, including the intestine where miR-29b facilitates TGF-β-mediated up-regulation of collagen in mucosal fibroblasts from Crohn’s disease (CD) patients. Myeloid cell leukemia-1 (MCL-1), a member of the B-cell CLL/Lymphoma 2 (BCL-2) apoptosis family, is involved in liver fibrosis and is targeted by miR-29b via its 3’-UTR in cultured cell lines. We investigate the role of MCL-1 and miR-29b in primary intestinal fibroblasts and tissue from stricturing CD patients. Transfection of CD intestinal fibroblasts with pre-miR-29b resulted in a significant increase in the mRNA expression of MCL-1 isoforms [MCL-1Long (L)/Extra Short (ES) and MCL-1Short (S)], although MCL-1S was expressed at significantly lower levels. Western blotting predominantly detected the anti-apoptotic MCL-1L isoform, and immunofluorescence showed that staining was localised in discrete nuclear foci. Transfection with pre-miR-29b or anti-miR-29b resulted in a significant increase or decrease, respectively, in MCL-1L foci. CD fibroblasts treated with IL-6 and IL-8, inflammatory cytokines upstream of MCL-1, increased the total mass of MCL-1L-positive foci. Furthermore, transfection of intestinal fibroblasts with pre-miR-29b resulted in an increase in mRNA and protein levels of IL-6 and IL-8. Finally, immunohistochemistry showed reduced MCL-1 protein expression in fibrotic CD samples compared to non-stricturing controls. Together, our findings suggest that induction of MCL-1 by IL-6/IL-8 may surmount any direct down-regulation by miR-29b via its 3’-UTR. We propose that an anti-fibrotic miR-29b/IL-6 IL-8/MCL-1L axis may influence intestinal fibrosis in CD. In the future, therapeutic modulation of this pathway might contribute to the management of fibrosis in CD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00441-017-2576-1) contains supplementary material, which is available to authorized users.
“…In addition, we have shown previously that miR-29b is anti-fibrotic in CD intestinal fibrosis (Nijhuis et al 2014). This accords well with both our observation here, that this miRNA up-regulates MCL-1L in fibroblasts, and the reported anti-fibrotic properties in the liver (Kahraman et al 2009; Vick et al 2009; Weng et al 2011). Hence, we hypothesised that the up-regulation of MCL-1L via miR-29b in intestinal CD fibroblasts is indirect.…”
Section: Discussionsupporting
confidence: 93%
“…However, these investigations did not identify the MCL-1 isoform directly. Deletion of the Mcl-1 gene in murine hepatocytes resulted in liver cell damage caused by spontaneous induction of apoptosis (Weng et al 2011). Evaluation of MCL-1 in CD intestinal fibrosis and any inter-action with miR-29b, remains to be investigated.Fig.…”
The miR-29 family is involved in fibrosis in multiple organs, including the intestine where miR-29b facilitates TGF-β-mediated up-regulation of collagen in mucosal fibroblasts from Crohn’s disease (CD) patients. Myeloid cell leukemia-1 (MCL-1), a member of the B-cell CLL/Lymphoma 2 (BCL-2) apoptosis family, is involved in liver fibrosis and is targeted by miR-29b via its 3’-UTR in cultured cell lines. We investigate the role of MCL-1 and miR-29b in primary intestinal fibroblasts and tissue from stricturing CD patients. Transfection of CD intestinal fibroblasts with pre-miR-29b resulted in a significant increase in the mRNA expression of MCL-1 isoforms [MCL-1Long (L)/Extra Short (ES) and MCL-1Short (S)], although MCL-1S was expressed at significantly lower levels. Western blotting predominantly detected the anti-apoptotic MCL-1L isoform, and immunofluorescence showed that staining was localised in discrete nuclear foci. Transfection with pre-miR-29b or anti-miR-29b resulted in a significant increase or decrease, respectively, in MCL-1L foci. CD fibroblasts treated with IL-6 and IL-8, inflammatory cytokines upstream of MCL-1, increased the total mass of MCL-1L-positive foci. Furthermore, transfection of intestinal fibroblasts with pre-miR-29b resulted in an increase in mRNA and protein levels of IL-6 and IL-8. Finally, immunohistochemistry showed reduced MCL-1 protein expression in fibrotic CD samples compared to non-stricturing controls. Together, our findings suggest that induction of MCL-1 by IL-6/IL-8 may surmount any direct down-regulation by miR-29b via its 3’-UTR. We propose that an anti-fibrotic miR-29b/IL-6 IL-8/MCL-1L axis may influence intestinal fibrosis in CD. In the future, therapeutic modulation of this pathway might contribute to the management of fibrosis in CD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00441-017-2576-1) contains supplementary material, which is available to authorized users.
“…Sirt1, a member of the mammalian sirtuin family, can regulate Nrf2 and p53 (Luo et al, 2001). It is well known that p53 is a well established sensor for DNA damage and cell death (Patel et al, 2010), which can promote apoptosis by regulating the levels of some apoptotic proteins including caspase-9, casepase-3 and Bcl-2 family (Weng et al, 2011), in which Bcl-2 family plays an important role to regulate mitochondrial signal pathway (Lee et al, 2006). Bak and some proapototic proteins can promote cell apoptosis, but Bcl-2 can inhibit apoptosis (Kong et al, 2012).…”
“…Conversely, conditional hepatocyte deletion of Mcl-1 in hepatocytes results in spontaneous hepatocyte apoptosis and liver injury (156, 361, 375). Mcl-1 is a protein highly regulated in cells given its short half-life and high protein turnover, affording multiple avenues to augments its cellular protein levels (116).…”
Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.
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