Homeostatic Role of Transforming Growth Factor-β in the Oral Cavity and Esophagus of Mice and Its Expression by Mast Cells in These Tissues

Abstract

Transforming growth factor-␤ (TGF-␤) is a pleiotropic growth factor; its overexpression has been implicated in many diseases, making it a desirable target for therapeutic neutralization. In initial safety studies, mice were chronically treated (three times per week) with high doses (50 mg/kg) of a murine, pan-neutralizing, anti-TGF-␤ antibody. Nine weeks after the initiation of treatment, a subset of mice exhibited weight loss that was concurrent with decreased food intake. Histopathology revealed a unique, nonneoplastic cystic epithelial hyperplasia and tongue inflammation, as well as dental dysplasia and epithelial hyperplasia and inflammation of both the gingiva and esophagus. In an effort to determine the cause of this site-specific pathology, we examined TGF-␤ expression in these tissues and saliva under normal conditions. By immunostaining, we found higher expression levels of active TGF-␤1 and TGF-␤3 in normal tongue and esophageal submucosa compared with gut mucosal tissues, as well as detectable TGF-␤1 in normal saliva by Western blot analysis. Interestingly, mast cells within the tongue, esophagus, and skin co-localized predominantly with the TGF-␤1 expressed in these tissues. Our findings demonstrate a novel and restricted pathology in oral and esophageal tissues of mice chronically treated with anti-TGF-␤ that is associated with basal TGF-␤ expression in saliva and by mast cells within these tissues. These studies illustrate a previously unappreciated biological role of TGF-␤ in maintaining homeostasis within both oral and esophageal tissues.

Transforming Growth Factor-β3 (TGF-β3) Knock-in Ameliorates Inflammation Due to TGF-β1 Deficiency While Promoting Glucose Tolerance

“…In our TGF-␤1 L␤3/L␤3 mice, the targeted exchange of the TGF-␤ isoforms actually resulted in reduced weight gain and suppressed fat accumulation. Inhibition of TGF-␤ signaling through the pan-specific anti-TGF-␤ antibody, 1D11, suppressed body weight gain in obese mice, in agreement with TGF-␤1's association with adiposity, yet a high dose of this same antibody resulted in hyperplasia and inflammation of the tongue and esophagus in various strains of mice (26,35). TGF-␤1 L␤3/L␤3 mice lacked any major signs of inflammation or hyperplasia over the course of their life spans.…”

“…Ϫ/Ϫ mice is multifocal inflammation that results in a wasting syndrome (12,13), and inhibition of the TGF-␤ signaling with a pan-specific antibody also leads to decreased food intake and weight loss through inflammation of the tongue and esophagus (35). To determine whether inflammation is responsible for decreased survival and reduced weight of the knock-in mice, we examined tissues from the TGF-␤1 L␤3/L␤3 mice at a time point when the TGF-␤1 Ϫ/Ϫ mice generally develop multifocal inflammation.…”

Transforming Growth Factor-β and Interleukin-1β Signaling Pathways Converge on the Chemokine CCL20 Promoter

“…Recent toxicity studies using pan-TGF-␤ antibody inhibitors fail to reveal evidence of systemic autoimmunity (50). To the contrary, antibody inhibition or condition genetic deletion of ␣v␤8-mediated TGF-␤ activation significantly inhibits lung inflammation, fibroinflammatory responses, and airway smooth muscle hyper-responsiveness in several preclinical models of asthma or COPD (6, 7).…”

Effects of Plasma Rich in Growth Factors on Bone Formation in Rat Calvaria

“…Briefly, PRGF fibrin membrane includes various growth factors such as TGF-β and VEGF involved in new bone formation stage 9,12) . TGF-β stimulates osteogenic differentiation in bone marrow mesenchymal stem cells 26,27) . VEGF is well known that promote angiogenesis in bone regeneration 28,29) .…”