Upregulation of activin signaling in experimental colitis

Abstract

Several lines of studies have suggested that activins are critical mediators of inflammation and tissue repair. As activins and their receptors are expressed in the gastrointestinal tract, we tested the hypothesis that activin signaling is involved in the development of colitis by using two murine models of colitis induced by dextran sodium sulfate (DSS) or in mdr1a-/- mice. By immunohistochemistry, expression of activins was found increased in both models and correlated with the severity of inflammation. Activin expression was observed in macrophages as well as in some nonmacrophage cells. Furthermore, while activin receptors are normally expressed in colonic epithelial cells, their expression was further increased in both epithelial cells and inflammatory cells in inflamed colonic mucosa. Moreover, in vitro studies showed that activin A inhibited proliferation and induced apoptosis of intestinal epithelial cells, and this growth inhibition was largely reversed by administration of the activin inhibitor, follistatin. Because we also observed an increased number of apoptotic epithelial cells in both colitis models, the upregulation of activins occurring in colitis could be involved both in the inflammatory process and in growth inhibition of the intestinal epithelium. Importantly, in vivo administration of follistatin attenuated inflammatory cell infiltration during colitis. Rectal bleeding was reduced, and the integrity of epithelium was preserved in the DSS/follistatin-treated group compared with the group treated with DSS alone. Bromodeoxyuridine incorporation studies showed an increase in proliferative epithelial cells in the DSS/follistatin-treated group, suggesting that follistatin accelerates epithelial cell proliferation/repair during colitis. Overall, our results reveal that activin signaling may play an important role in the pathogenesis and resolution of colitis. These findings suggest new therapeutic options in inflammatory bowel diseases.

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer

“…In vitro studies have shown that activin βA-subunit is expressed in epithelial cells from human embryonic and rat small intestinal cells [37, 38]. Exogenous activin-A inhibited cell proliferation and induced differentiation of rat IEC-6 cells [37], decreased the growth of mice m-ICc12 cells [39] while stimulated the proliferation of colonic epithelial cells collected from developing rats [40]. Nevertheless, others failed to detect activin βA-subunit and/or showed weak immunostain in normal human colonic tissues despite the localisation of activin receptors within the same samples [19, 41].…”

“…Similarly, studies in mice also reported weak or no expression of βA-subunit in normal colonic glands and the induction of colitis resulted in a significant increase of the molecule [39, 42]. The expression of both type IIA and IIB receptors as well as smads 2&3 has also been detected in mice normal colon epithelial cells and, a significant increase in their production was noted during colitis and they were co-localised with activin subunits within the same cells [39].…”

“…Similarly, studies in mice also reported weak or no expression of βA-subunit in normal colonic glands and the induction of colitis resulted in a significant increase of the molecule [39, 42]. The expression of both type IIA and IIB receptors as well as smads 2&3 has also been detected in mice normal colon epithelial cells and, a significant increase in their production was noted during colitis and they were co-localised with activin subunits within the same cells [39]. Injecting follistatin in vivo also inhibited the progress of inflammation [39, 42], while overexpression of activin-A in vivo following injection of a plasmid DNA containing βA-subunit cDNA in mice resulted in sever intestinal inflammation [43].…”

“…The expression of both type IIA and IIB receptors as well as smads 2&3 has also been detected in mice normal colon epithelial cells and, a significant increase in their production was noted during colitis and they were co-localised with activin subunits within the same cells [39]. Injecting follistatin in vivo also inhibited the progress of inflammation [39, 42], while overexpression of activin-A in vivo following injection of a plasmid DNA containing βA-subunit cDNA in mice resulted in sever intestinal inflammation [43]. Notably, weak intraepithelial localisation of βB-subunit in normal colon has been reported by a single study and the expression increased during colitis and was co-localised with the βA-subunit [39].…”

Role of activin-A in cigarette smoke-induced inflammation and COPD

“…Administration of follistatin C57BL/6 mice were injected intraperitoneally with 1 mg of recombinant mouse follistatin-288 (R&D Systems) or PBS (controls) [26]. Mice were injected three times a week in a subacute (4 weeks) cigarette smoke experiment, 30 min before air or cigarette smoke exposure.…”