Direct Evidence for Cytokine Involvement in Neointimal Hyperplasia

BackgroundTumor necrosis factor-&agr; (TNF-&agr;) 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-&agr; 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-&agr; and IL-1 modulate low shear stress–induced NIH. Methods and ResultsMice 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-&agr; and IL-1&agr; mRNA demonstrated both TNF-&agr; and IL-1&agr; mRNA in ligated CCAs, whereas normal and sham-operated CCAs had none. Mice lacking functional TNF-&agr; (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-1&agr; mRNA expression was detected in CCAs from TNF−/− mice; however, TNF-&agr; mRNA expression was found in the IL-1RI−/− mice. Mice that overexpress membrane-bound TNF-&agr; but produce no soluble TNF-&agr; display an accentuated fibroproliferative response to low shear stress (P <0.05). ConclusionsThese results directly demonstrate that TNF-&agr; and IL-1 modulate NIH induced by low shear stress. NIH can proceed by way of soluble TNF-&agr;–independent mechanisms. Specific anti–TNF-&agr; and anti–IL-1 therapies may lessen NIH.

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