Direct evidence for cytokine involvement in neointimal hyperplasia

John E. Rectenwald, Lyle L. Moldawer, Thomas S. Huber, James M. Seeger, C. Keith Ozaki

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

Abstract

Background - Tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) are proximal inflammatory cytokines that stimulate expression of adhesion molecules and induce synthesis of other proinflammatory cytokines. In addition, TNF-α and IL-1 influence vascular smooth muscle cell migration and proliferation in vitro. In view of the inflammatory nature of neointimal hyperplasia (NIH), we tested the hypothesis that endogenous TNF-α and IL-1 modulate low shear stress-induced NIH. Methods and Results - Mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated CCA has previously been shown to result in remodeling and NIH. Reverse transcriptase-polymerase chain reaction for TNF-α and IL-1α mRNA demonstrated both TNF-α and IL-1α mRNA in ligated CCAs, whereas normal and sham-operated CCAs had none. Mice lacking functional TNF-α (TNF-/-) developed 14-fold less neointimal area than WT controls (P<0.05). p80 IL-1 type I receptor knockout (IL-1RI-/-) mice tended to develop less (7-fold, P>0.05) neointimal area than WT controls. Furthermore, no IL-1α mRNA expression was detected in CCAs from TNF-/- mice; however, TNF-α mRNA expression was found in the IL-1RI-/- mice. Mice that overexpress membrane-bound TNF-α but produce no soluble TNF-α display an accentuated fibroproliferative response to low shear stress (P<0.05). Conclusions - These results directly demonstrate that TNF-α and IL-1 modulate NIH induced by low shear stress. NIH can proceed by way of soluble TNF-α-independent mechanisms. Specific anti-TNF-α and anti-IL-1 therapies may lessen NIH.

Original languageEnglish (US)
Pages (from-to)1697-1702
Number of pages6
JournalCirculation
Volume102
Issue number14
DOIs
StatePublished - Oct 3 2000

Keywords

  • Atherosclerosis
  • Carotid arteries
  • Remodeling
  • Restenosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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