MANF protects pancreatic acinar cells against alcohol‐induced endoplasmic reticulum stress and cellular injury

Abstract

Alcohol consumption has long been recognized as a risk factor for pancreatitis, including both acute pancreatitis and chronic pancreatitis. 1 Pancreatitis is an inflammatory disorder characterized by acinar cell injury and death. 2 Epidemiological studies have shown that the risk of developing pancreatitis is positively correlated to the amount of alcohol intake

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

“…In contrast to the role of MANF in the endocrine function of the pancreas which has been well characterized, the role of MANF in the exocrine compartment of pancreas has not drawn much attention until very recently. Using an in vitro model, we showed an siRNA knockdown of MANF exacerbated alcohol-induced damages in mouse pancreatic 266-6 acinar cells; whereas addition of recombinant human MANF or overexpression of MANF by adenovirus ameliorated alcoholinduced ER stress and cellular injury 229 . While this finding may imply a beneficial role for MANF in alcoholic pancreatitis, further studies of measuring the effect of gain-or loss-of-function of MANF on pancreatitis features in animal alcoholic pancreatitis are necessary.…”

“…These inhibitors, including toyocamycin, 3-Ethoxy-5,6-dibromosalicylaldehyde, STF-083010 and 2-Hydroxy-1-naphthaldehyde, have been shown to induce apoptosis in a number of pancreatic tumor cell lines 228 . Of note, STF-083010 has been shown to protect mouse pancreatic 266-6 acinar cells from alcohol-induced cytotoxicity in vitro 229 (Fig. 3).…”

“…MANF is an ER stress-inducible secretory protein expressed in many human and mouse tissues, with a particularly high expression level in secretory tissues such as the pancreas 286,287 . MANF is activated by alcohol exposure and plays a protective role by alleviating alcohol-induced ER stress in the brain and in cultured acinar cells 199,229,288 (Fig. 3).…”

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

“…These inhibitors, including toyocamycin, 3-ethoxy-5,6-dibromosalicylaldehyde, STF-083010, and 2-hydroxy-1-naphthaldehyde, have been shown to induce apoptosis in a number of pancreatic tumor cell lines [ 241 ]. Of note, STF-083010 has been shown to protect mouse pancreatic 266-6 acinar cells from alcohol-induced cytotoxicity in vitro [ 210 ] ( Figure 3 ). Another inhibitor belonging to the first group, MKC-3946, was shown to cause cell death in rat pancreatic AR42J acinar cells, primary mouse, and human acinar cells in vitro [ 132 ].…”

“…MANF is an ER-stress-inducible secretory protein expressed in many human and mouse tissues, with a particularly high expression level in secretory tissues such as the pancreas [ 286 , 287 ]. MANF is activated by alcohol exposure and plays a protective role by alleviating alcohol-induced ER stress in the brain and in cultured acinar cells [ 210 , 224 , 288 ] ( Figure 3 ). The cytoprotective role of MANF in the pancreas has been demonstrated by the increased apoptosis and reduced proliferation of pancreatic beta cells and an insulin-deficient phenotype in pancreatic MANF knockout mice [ 289 , 290 ].…”