Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia. |
| |
Authors: | John E Rectenwald Rebecca M Minter Lyle L Moldawer Zaher Abouhamze Drake La Face Elizabeth Hutchins Thomas S Huber James M Seeger C Keith Ozaki |
| |
Institution: | University of Florida College of Medicine, Gainesville, Florida 32610, USA. |
| |
Abstract: | INTRODUCTION: Overexpression of the anti-inflammatory cytokine interleukin-10 (IL-10) blocks atherosclerotic events in vivo, and IL-10 has been recently hailed as an "immunologic scalpel" for atherosclerosis. Alternatively, mice lacking IL-10 receiving atherogenic diets have increased occlusive lesions. It remains unclear whether such IL-10 modulation broadly applies to other forms of occlusive arterial remodeling. We hypothesized that lack of IL-10 would exacerbate, and exogenous or overexpression of IL-10 would abrogate low shear stress-induced neointimal hyperplasia (NIH). METHODS: Wild-type (WT) and IL-10-deficient (IL-10-/-) mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated artery results in remodeling and formation of neointima containing BrdU and SMC alpha-actin-positive cells. Additional groups of WT mice underwent CCA ligation and were treated daily with intraperitoneal saline or 1 microg of human IL-10. Chronic delivery gene therapy approaches were also utilized to define the role of IL-10 signaling. WT mice were treated adventitially with 1 x 10(10) adenovirus/green fluorescent protein (Ad/gfp) and an Ad/empty control to confirm the veracity of adventitial delivery. Then, Ad viral IL-10 (vIL-10), Ad/empty, and virus buffer alone were applied directly to the adventitia of the CAA immediately following ligation. In separate experiments, 1 x 10(10) Ad/empty or Ad/vIL-10 was injected intramuscularly. CCAs were perfusion fixed 28 days postligation, the time at which NIH is near maximum. RESULTS: IL-10-/- mice developed identical NIH areas compared to WT controls. Mice receiving IL-10 demonstrated NIH equivalent to saline controls. Mice receiving intramuscular or adventitial Ad/IL-10 developed high serum levels of IL-10 yet formed NIH areas similar to those of controls. Serum IL-10 levels were significantly higher (P = 0.04) with adventitial delivery. Mice treated adventitially with Ad/gfp showed reliable transfection of cells within the adventitia of CAA. No antibody to human IL-10 was found in the sera of intraperitoneal IL-10-treated mice, which failed to attenuate NIH. CONCLUSION: Under the conditions of this experiment, lack of IL-10 does not exacerbate low shear stress-induced NIH, nor does exogenous administration or overexpression of IL-10 attenuate it. Despite high serum levels of vIL-10 in mice treated with ad/vIL-10 adventitially, there appears to be no therapeutic effect despite the confirmed transfection of adventitial cells. Discrepancies between these findings and previous research may be related to IL-10 dosing, inflammation induced by the adenoviral vector, or disparities between the NIH models. |
| |
Keywords: | neointimal hyperplasia interleukin 10 adenovirus gene therapy arterial remodeling atherosclerosis |
本文献已被 ScienceDirect 等数据库收录! |
|