title: Inflammatory cytokines promote growth of intestinal smooth muscle cells by induced expression of PDGF-Rβ.
abstract: Thickening of the inflamed intestinal wall involves growth of smooth muscle cells (SMC), which contributes to stricture formation. Earlier, the growth factor platelet-derived growth factor (PDGF)-BB was identified as a key mitogen for SMC from the rat colon (CSMC), and CSMC growth in colitis was associated with both appearance of its receptor, PDGF-Rβ and modulation of phenotype. Here, we examined the role of inflammatory cytokines in inducing and modulating the growth response to PDGF-BB. CSMC were enzymatically isolated from Sprague-Dawley rats, and the effect of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, transforming growth factor (TGF), IL-17A and IL-2 on CSMC growth and responsiveness to PDGF-BB were assessed using proliferation assays, PCR and western blotting. Conditioned medium (CM) was obtained at 48 hrs of trinitrobenzene sulphonic acid-induced colitis. Neither CM alone nor cytokines caused proliferation of early-passage CSMC. However, CM from inflamed, but not control colon significantly promoted the effect of PDGF-BB. IL-1β, TNF-α and IL-17A, but not other cytokines, increased the effect of PDGF-BB because of up-regulation of mRNA and protein for PDGF-Rβ without change in receptor phosphorylation. PDGF-BB was identified in adult rat serum (RS) and RS-induced CSMC proliferation was inhibited by imatinib, suggesting that blood-derived PDGF-BB is a local mitogen in vivo. In freshly isolated CSMC, CM from the inflamed colon as well as IL-1β and TNF-α induced the early expression of PDGF-Rβ, while imatinib blocked subsequent RS-induced cell proliferation. Thus, pro-inflammatory cytokines both initiate and maintain a growth response in CSMC via PDGF-Rβ and serum-derived PDGF-BB, and control of PDGF-Rβ expression may be beneficial in chronic intestinal inflammation.
authors.affiliation: Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Dileep G
authors.initials: DG
authors.lastname: Nair
authors.forename: Kurtis G
authors.initials: KG
authors.lastname: Miller
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Lourenssen
authors.forename: Michael G
authors.initials: MG
authors.lastname: Blennerhassett
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000494:pharmacology*; D007422:Intestines / Q000473:pathology*; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D018836:Inflammation Mediators; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: PDGF; TNBS; colitis; mitosis; phenotype; smooth muscle; stricture