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* Department of Surgery and
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455; and
Veterans Administration and Department of Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
Vascular endothelial cells (ECs) can be injured in a variety of pathologic processes that involve activated complement. We reported previously that porcine ECs incubated with exogenous IL-4 or IL-13 are protected from cytotoxicity by human complement and also from apoptosis by TNF-
. The resistance to complement consists of an intrinsic mechanism that is lost a few days after cytokine removal. In our current study, we investigated whether transfer of the IL-4 gene into porcine ECs in vitro and into porcine vascular tissues in vivo would induce efficient and durable protection from human complement. We found that ECs transduced with adenoIL-4 or adenoIL-13 exhibited continuous production of the cytokine and prolonged protection from complement-mediated killing. IL-4 also protected ECs from activation: ECs incubated with IL-4 did not develop cell retraction and intercellular gaps upon stimulation with sublytic complement. The endothelium and subendothelium of pig iliac arteries that were transduced with the IL-4 gene were effectively protected from complement-dependent immediate injury after perfusion with human blood. However, after similar perfusion, the endothelium was immediately lost from arteries that were transduced with a control adenovirus. The protection was not due to up-regulation of the complement regulators decay accelerating factor, membrane cofactor protein, and CD59, or to reduced complement activation, but required the participation of Akt. Although our studies model protection in pig-to-primate xenotransplantation, our findings of IL-4 induction of Akt-mediated protection may be more broadly applicable to EC injury as manifested in ischemia-reperfusion, allotransplantation, and various vascular diseases.
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1 This work was supported in part by National Institutes of Health Grant R01HL62195; a grant from the Lillehei Heart Institute, University of Minnesota (to A.P.D.); National Research Service Awards 1F32AI066741 (to S.M.B.) and 1F32DK10006 (to J.F.G.); National Institutes of Health Training Grant T32HL07934; a Richard A. Varco Surgical Fellowship Award; and National Cancer Institute Grant P30CA77598. A.E.K. was supported by funds from the Veterans Administration, National Institutes of Health Grants R01AI40987 and AR48267, and the Frederick G. L. Huetwell and William D. Robinson, M. D. Professorship of Rheumatology.
2 Address correspondence and reprint requests to Dr. Agustin P. Dalmasso, Department of Surgery, Mayo Mail Code 220, University of Minnesota, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail address: dalma001{at}umn.edu
3 Abbreviations used in this paper: MAC, membrane attack complex of complement; EC, endothelial cell; DAF, decay accelerating factor; MOI, multiplicity of infection; DNAkt, dominant-negative inactive Akt; RT, room temperature; MCP, membrane cofactor protein; NSS-BSA, isotonic saline containing 0.1% BSA and 2 U/ml heparin.
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