Interleukin-10 Attenuates the Response to Vascular Injury 1,2 Michael A. Zimmerman, M.D.,* Leonid L. Reznikov, M.D.,* Christopher D. Raeburn, M.D.,* and Craig H. Selzman, M.D.* ,†,3 *Department of Surgery, University of Colorado Health, Sciences Center, Denver, Colorado; and †Division of Cardiothoracic Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Submitted for publication February 4, 2004 Background. The inflammatory response to vascular injury is characterized by expression of cytokines, growth factors, and chemokines that conspire to pro- mote vessel remodeling and intimal hyperplasia (IH). Interleukin-10 (IL-10) is a multifunctional cytokine that has several anti-inflammatory properties in vitro. Few studies have evaluated the effects of IL-10 in ex- perimental atherosclerosis. The purpose of the present study was to determine the influence of IL-10 on vascular inflammation and IH following mechani- cal injury. Methods. Wire carotid injury was performed in wild- type (WT) mice with and without IL-10 treatment. Immu- nohistochemistry, PCR, and ELISA assays were used to examine vessel production of basic fibroblast growth factor (bFGF), monocyte chemotactic protein-1 (MCP-1), and nuclear factor kappa B (NFB). Vessels were mor- phometrically analyzed for IH. Results. Carotid injury induced early expression of MCP-1 and bFGF that was abrogated in mice treated with IL-10. Similarly, injury-induced expression of NFB message and protein was attenuated in mice receiving exogenous IL-10. Compared to untreated mice, IL-10 markedly decreased levels of IH. Interest- ingly, carotid injury in IL-10-deficient mice resulted in an augmented IH response compared to injured WT mice. Conclusions. In an in vivo model of direct vascular injury, IL-10 decreased expression of the pro-inflam- matory transcription factor, NFB, and the mitogenic chemokine and growth factor, MCP-1 and bFGF, respec- tively. These observations were associated with IL-10- induced attenuation of IH. Furthermore, endogenous IL-10 appeared to suppress the injury response. In con- clusion, exogenously delivered IL-10 may represent a clinically relevant anti-inflammatory strategy for post- injury intimal hyperplasia. © 2004 Elsevier Inc. All rights reserved. Key Words: interleukin-10; intimal hyperplasia. INTRODUCTION Accumulating data suggest a profound role for in- flammation in the development of intimal hyperplasia (IH) [1–3]. Following vascular injury, resident and cir- culating vascular cells secrete and respond to a wide array of cytokines, growth factors, and chemokines. These mediators orchestrate macrophage infiltration and vascular smooth muscle (VSMC) proliferation and migration. Together, these actions conspire to promote IH. As such, anti-inflammatory strategies targeting this response to injury are conceptually attractive. Interleukin-10 (IL-10) is an anti-inflammatory cyto- kine produced by several vascular cell types including lymphocytes, monocytes/macrophages, endothelial cells, and VSMC [4, 5]. Several studies have examined the effects of IL-10 on vascular events in vitro. IL-10 de- creased human monocyte expression of intracellular ad- hesion molecule-1 [6], decreased production of reactive oxygen intermediates [7], and decreased antigen presen- tation to T-lymphocytes [8]. In addition, we have previ- ously demonstrated that physiological doses of IL-10 in- hibited mitogen-induced human VSMC proliferation [9]. The anti-inflammatory effects of IL-10 are, in part, asso- ciated with inhibition of the transcription factor nuclear factor kappa-B (NFB) [10]. Cumulatively, these in vitro studies suggest that IL-10 might beneficially inhibit ves- sel wall inflammation. 1 Supported by a grant from the Pacific Vascular Research Foun- dation (C.H.S.). 2 This manuscript is not under consideration elsewhere. None of this paper’s contents have been previously published. All authors have read and approved the manuscript. We have no conflicts of interest that require disclosure. 3 To whom correspondence and reprint requests should be ad- dressed at University of North Carolina at Chapel Hill, Division of Cardiothoracic Surgery, Medical School Wing C, Room 354, CB# 7065, Chapel Hill, NC 27599-7065. E-mail: selzman@med.unc.edu. Journal of Surgical Research 121, 206 –213 (2004) doi:10.1016/j.jss.2004.03.025 206 0022-4804/04 $30.00 © 2004 Elsevier Inc. All rights reserved.