Direct evidence for cytokine involvement in neointimal hyperplasia

• Published in: Circulation (New York, N.Y.) Vol. 102; no. 14; pp. 1697 - 1702
• Main Authors: RECTENWALD, John E, MOLDAWER, Lyle L, HUBER, Thomas S, SEEGER, James M, OZAKI, C. Keith
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 03.10.2000; American Heart Association, Inc
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Hyperplasia - metabolism; Immunohistochemistry; Interleukin-1 - genetics; Interleukin-1 - metabolism; Interleukin-1 - physiology; Male; Medical sciences; Mice; Mice, Transgenic; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology; Tunica Intima - metabolism; Tunica Intima - pathology; Pathogenesis; Hyperplasia; Rodentia; Cytokine; Cardiovascular disease; Vascular disease; Vertebrata; Mammalia; Mouse; Animal; Carotid; Atherosclerosis; Interleukin 1; Intima; Tumor necrosis factor α
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.102.14.1697

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