title: Interleukin-10 inhibits postinjury tumor necrosis factor-mediated human vascular smooth muscle proliferation.
abstract: BACKGROUND
  Both ischemic and direct vascular injury (angioplasty) result in the elaboration of proinflammatory substances, including tumor necrosis factor alpha (TNF), which may regulate vascular smooth muscle cell (VSMC) proliferation and promote vessel stenosis. Interleukin-10 (IL-10) is a pleiotropic cytokine with potent antiinflammatory effects in many cells lines. We hypothesized that IL-10 could be used therapeutically to influence vascular remodeling by inhibiting TNF-induced VSMC proliferation. The purposes of this study were (1) to determine whether human myocardium produces endogenous TNF in response to ischemia-reperfusion, (2) to examine the effect of TNF on human arterial smooth muscle proliferation, and (3) to explore the potential therapeutic effect of IL-10 on unstimulated and TNF-stimulated VSMC proliferation.
  
  
  METHODS
  Right atrial muscle was obtained from patients undergoing elective cardiac surgery. Atrial muscle was subjected to simulated ischemia and reperfusion in vitro and TNF was measured by immunoassay. Human aortic VSMCs were isolated and cultured. Proliferation assays were performed to determine the effect of TNF and IL-10 on VSMC growth.
  
  
  RESULTS
  Ischemia-reperfusion resulted in an increase in atrial myocellular TNF (94.5 +/- 15.8 pg/g wet tissue versus control 12.9 +/- 4.4 pg/g wet tissue, P < 0.002). Compared with control, TNF stimulated concentration-dependent VSMC proliferation (P < 0.005). IL-10 alone did not influence VSMC growth. However, following TNF stimulation, IL-10 inhibited VSMC growth at a dose as low as 0.1 pg/ml (P < 0.005).
  
  
  CONCLUSIONS
  Ischemia-reperfusion insult results in increased endogenous myocardial TNF accumulation. TNF stimulates VSMC growth which is abrogated by physiologically relevant levels of IL-10. This antiinflammatory cytokine may prove to be an effective therapeutic agent in regulating vessel wall remodeling following both ischemic and direct cardiovascular injury.
authors.affiliation: Department of Surgery, University of Colorado Health Sciences Center, and The Veterans Affairs Hospital, Denver, Colorado, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Selzman
authors.forename: D R
authors.initials: DR
authors.lastname: Meldrum
authors.forename: B S
authors.initials: BS
authors.lastname: Cain
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.forename: B D
authors.initials: BD
authors.lastname: Shames
authors.forename: L
authors.initials: L
authors.lastname: Ao
authors.forename: A H
authors.initials: AH
authors.lastname: Harken
mesh_terms: D017130:Angioplasty / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006325:Heart Atria / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000494:pharmacology* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10