Therapeutic potential of follistatin for colonic inflammation in mice.
OBJECTIVE
Activins belong to the transforming growth factor-beta superfamily. Recent studies have shown that activin and its natural antagonist, follistatin, are involved in tissue repair and inflammatory processes. The aim of this study was to determine whether neutralization of activins with follistatin would have an in vivo anti-inflammatory effect in several murine models of colitis.


METHODS
We assessed activin levels in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid (TNBS). We subsequently tested the effects of an intraperitoneal injection of follistatin before or after induction of TNBS colitis. We also examined the established colitis induced by oral dextran sulfate sodium (DSS) as well as the spontaneous colitis that develops in interleukin (IL)-10 gene-deficient (IL-10 -/- ) mice.


RESULTS
Levels of activin transcripts in the colon during the acute phase of TNBS colitis were up-regulated. Epithelial cells, infiltrating macrophages (Mvarphi), and endothelial cells produced excess activin betaA. Pretreatment with follistatin increased the survival rate of mice with TNBS colitis from 33% to 82% and decreased the plasma levels of IL-6 and amyloid A. Administration of follistatin also reduced the histologic score and tissue myeloperoxidase activity in established TNBS and DSS colitis and reduced the severity of the colitis in IL-10 -/- mice. Based on results obtained from 3 mouse models and from in vitro experiments, follistatin promoted the proliferation of colonic epithelial cells.


CONCLUSIONS
Neutralization of activins by follistatin promoted epithelial cell division and tissue repair, clearly suggesting a treatment modality for intestinal inflammation.
Dohi
Taeko
T
Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo. dohi@ri.imcj.go.jp
Ejima
Chieko
C
Kato
Rie
R
Kawamura
Yuki I
YI
Kawashima
Rei
R
Mizutani
Noriko
N
Tabuchi
Yoshiaki
Y
Kojima
Itaru
I
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D003108:Colonic Diseases / Q000188:drug therapy*; D005260:Female; D038681:Follistatin / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid
D038681:Follistatin; D012333:RNA, Messenger; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase