Expression of Transforming Growth Factor-β₁ in Chronic Pancreatitis

Abstract

Transforming growth factor-β₁ (TGF-β₁) is a multifunctional cytokine which modifies tissue stromal matrix synthesis, cell proliferation and immune function. In the present study, we have used a mouse monoclonal antibody to the latent (intracytoplasmic) form of TGF-β₁ to compare its expression in 144 cases of human chronic pancreatitis (both obstructive and chronic calcifying) with that of 10 control pancreatic specimens. In all the control specimens, and most of those with chronic pancreatitis, cytoplasmic immunoreactivity was identified in pancreatic duct and ductular epithelium, in islet cells and in vascular smooth muscle and endothelium. Two distinct patterns of ductular epithelial staining emerged: in morphologically normal tissues, only individual distal ductular/centroacinar cells stained but in chronic pancreatitis (whether chronic calcifying or chronic obstructive) the staining was panductular. Positive cytoplasmic immunostaining of acinar epithelial cells was found in 3% of pancreatitis specimens but in none of the normal controls. There was no staining of fibroblasts. Synthesis of TGF-β₁ appears to be normally restricted to a population of epithelial cells located in terminal/centroacinar regions of the ductules (together with occasional ductal cells) whereas in chronic pancreatitis, TGF-β₁ is expressed in most ductular and ductal epithelial cells.

Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells.

“…In light of the results reported in this study, it becomes important to consider the potential participation of TIEG in TGF␤-mediated signaling cascades that regulate cell growth not only during embryogenesis but also during the development of pancreatic diseases (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). As stated earlier, both chronic pancreatitis and pancreatic cancer are often accompanied by alterations in these signaling cascades.…”

“…As stated earlier, both chronic pancreatitis and pancreatic cancer are often accompanied by alterations in these signaling cascades. For instance, high levels of TGF␤ peptides have been implicated in the development of fibrosis in both diseases, and probably contribute to the epithelial atrophy found in chronic pancreatitis (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In addition, a recently identified candidate tumor suppressor gene for pancreatic cancer, DPC4, has been shown to belong to a family of proteins involved in TGF␤-mediated signaling from insects to vertebrates (14,(45)(46)(47).…”

“…Interestingly, alterations in TGF ␤ -mediated signaling cascades are often found in pancreatic diseases. For instance, an upregulation in the expression of several members of this family of peptide growth factors is found in chronic pancreatitis, and this alteration has been proposed to participate in the development of both the fibrosis and the parenchymal atrophy that are landmarks of this disease (6)(7)(8)(9)(10)(11). This observation is further supported by the fact that transgenic animals overexpressing TGF ␤ 1 develop pancreatic lesions compatible with chronic pancreatitis (7,9).…”

Pressure activates rat pancreatic stellate cells

“…This is in agreement with the previous study (43) in rat HSCs that mechanical force induces TGF-␤ synthesis. TGF-␤1 plays a profibrotic role in a variety of organs including the liver, kidneys, and pancreas (14,22,45,49). Overexpression of TGF-␤1 has been revealed in human chronic pancreatitis (17,45,49).…”

“…TGF-␤1 plays a profibrotic role in a variety of organs including the liver, kidneys, and pancreas (14,22,45,49). Overexpression of TGF-␤1 has been revealed in human chronic pancreatitis (17,45,49). Transgenic mice overexpressing TGF-␤ in islet cells develop fibrosis of the exocrine pancreas.…”