title: Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells.
abstract: Growth hormone (GH) and IGF-I play important roles in wound healing during intestinal injury and inflammation, but there is also indirect evidence that locally expressed IGF-I may act to induce excessive collagen deposition, which can lead to intestinal fibrosis. Factors that dictate the balance between normal wound healing and excessive healing responses are unknown. Using RNase protection assay and in situ hybridization, we determined whether GH and/or IGF-I increase type I collagen deposition in the intestine of rats fed by total parenteral nutrition (TPN), a feeding modality used for many patients following intestinal surgery and resection. We also used an in vitro model system to confirm our in vivo effects and to directly evaluate the relative potency of GH and IGF-I on DNA synthesis and collagen deposition in intestinal myofibroblasts. Both GH and IGF-I stimulated collagen production in vivo and in vitro, and IGF-I, but not GH, stimulated DNA synthesis in vitro. In collagen production, GH was less potent than IGF-I. Suppressors of cytokine signaling (SOC) are cytokine-inducible proteins that negatively feedback to inhibit the actions of cytokines and we recently found that GH selectively upregulates SOC-2 in the intestine of TPN-fed rats. We examined whether SOC-2 may be responsible for the difference in magnitude of action of GH and IGF-I on collagen accumulation. GH, but not IGF-I, induced SOC-2 in isolated myofibroblasts, and overexpression of SOC-2 led to a suppression of GH- and IGF-I-induced collagen accumulation. SOC-2 null mice infused with IGF-I showed greater collagen gene expression compared with wild-type (WT) mice. Myofibroblasts isolated from SOC-2 null mice showed increased IGF-I-stimulated DNA synthesis compared with WT cells. Taken together, these findings suggest that SOC-2 induced by GH may play an important role in suppressing collagen accumulation and mesenchymal cell proliferation induced by GH or GH-induced IGF-I, providing a mechanism for the differing potencies of GH and IGF-I on intestinal mesenchyme and collagen synthesis.
authors.affiliation: Dept. of Cell and Molecular Physiology, CB#7545, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599-7545, USA.
authors.forename: Shira
authors.initials: S
authors.lastname: Fruchtman
authors.forename: James G
authors.initials: JG
authors.lastname: Simmons
authors.forename: Carmen Z
authors.initials: CZ
authors.lastname: Michaylira
authors.forename: Megan E
authors.initials: ME
authors.lastname: Miller
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Greenhalgh
authors.forename: Denise M
authors.initials: DM
authors.lastname: Ney
authors.forename: P Kay
authors.initials: PK
authors.lastname: Lund
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis; D013006:Growth Hormone / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007583:Jejunum / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; 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*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C491408:Socs2 protein, rat; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D004247:DNA