Upregulation of activin signaling in experimental colitis.
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.
Zhang
You-Qing
YQ
Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Resta
Silvia
S
Jung
Barbara
B
Barrett
Kim E
KE
Sarvetnick
Nora
N
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D029404:Activin Receptors / Q000235:genetics / Q000378:metabolism*; D028341:Activins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D038681:Follistatin / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; C503233:FST protein, human; D038681:Follistatin; D011994:Recombinant Proteins; C422405:activin A; D028341:Activins; D016264:Dextran Sulfate; C095122:multidrug resistance protein 3; D029404:Activin Receptors