Suppressor of cytokine signaling-2: a growth hormone-inducible inhibitor of intestinal epithelial cell proliferation.
OBJECTIVE
Growth hormone (GH) and insulin-like growth factor-I (IGF-I) increase intestinal growth. GH is thought to act indirectly via IGF-I. In several models, including rats given total parenteral nutrition (TPN), IGF-I more potently stimulates mucosal growth than GH, even when GH induces similar circulating IGF-I levels. These studies test the hypothesis that GH induces a suppressor of cytokine signaling (SOCS), which inhibits intestinal epithelial cell (IEC) proliferation.


METHODS
Rats on TPN received vehicle, GH, or IGF-I. Jejunal SOCS (SOCS-1, -2, -3, and cytokine-inducible SH2-domain-containing protein [CIS]) and IGF-I messenger RNA (mRNA) were quantified. Caco-2, IEC-6 cells, and SOCS-2 null and wild-type (WT) mice were used to examine the expression and functional role of SOCS-2.


RESULTS
As reported previously, IGF-I, but not GH, prevented mucosal atrophy during TPN, although GH elevated plasma IGF-I and increased body weight. GH, but not IGF-I, induced jejunal SOCS-2 mRNA. SOCS-2 mRNA levels in GH and IGF-I-treated rats inversely correlated with mucosal weight. SOCS-2 is expressed in Caco-2 cells, and elevated SOCS-2 expression in postconfluent cells is associated with reduced proliferative rates. SOCS-2 overexpression in Caco-2 cells inhibited cell proliferation and promoted differentiation. In IEC-6 cells, GH induced SOCS-2 and reduced basal or IGF-I-induced proliferation. GH also reduced proliferative activity in isolated crypts from WT but not SOCS-2 null mice, and SOCS-2 null crypts showed enhanced proliferative responses to GH and IGF-I. SOCS-2 null mice have increased intestinal weight and length.


CONCLUSIONS
SOCS-2 is a GH-inducible, novel inhibitor of intestinal epithelial cell proliferation and intestinal growth.
Miller
Megan E
ME
Department of Nutrition, University of North Carolina at Chapel Hill, 27599-7545, USA.
Michaylira
Carmen Z
CZ
Simmons
James G
JG
Ney
Denise M
DM
Dahly
Elizabeth M
EM
Heath
Joan K
JK
Lund
P Kay
PK
D000818:Animals; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003106:Colon / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives*; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D007583:Jejunum / Q000166:cytology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010289:Parenteral Nutrition, Total; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C106643:SOCS2 protein, human; C491409:Socs2 protein, mouse; C491408:Socs2 protein, rat; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007987:Gonadotropin-Releasing Hormone; D007334:Insulin-Like Growth Factor I; C040278:MI 1544; D013006:Growth Hormone