Inflammatory cytokines promote growth of intestinal smooth muscle cells by induced expression of PDGF-Rβ

Authors

  • Dileep G. Nair,

    1. Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada
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  • Kurtis G. Miller,

    1. Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada
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  • Sandra R. Lourenssen,

    1. Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada
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  • Michael G. Blennerhassett

    Corresponding author
    1. Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada
    • Correspondence to: M. G. BLENNERHASSETT, Ph.D., Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, 76 Stuart St, Kingston, Ontario, Canada.

      Tel.: 613 549 6666 x6523

      Fax: 613 548 2426

      E-mail: blennerm@queensu.ca

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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.

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