Interleukin 10 Attenuates Neointimal Proliferation and Inflammation in Aortic Allografts by a Heme Oxygenase-Dependent Pathway

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 20; pp. 7251 - 7256
• Main Authors: Chen, Sifeng, Kapturczak, Matthias H., Wasserfall, Clive, Glushakova, Olena Y., Campbell-Thompson, Martha, Deshane, Jessy S., Joseph, Reny, Cruz, Pedro E., Hauswirth, William W., Madsen, Kirsten M., Croker, Byron P., Berns, Kenneth I., Atkinson, Mark A., Flotte, Terence R., Tisher, C. Craig, Agarwal, Anupam
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17-05-2005; National Acad Sciences
• Subjects: Analysis of Variance; Animals; Aorta - transplantation; Biological Sciences; Blotting, Western; Cell Proliferation; Cytokines; Dependovirus; Endothelial Cells - cytology; Enzyme-Linked Immunosorbent Assay; Enzymes; Genetic Vectors; Graft rejection; Graft Rejection - metabolism; Graft Rejection - prevention & control; Heart; Heat-Shock Proteins - metabolism; Heme Oxygenase (Decyclizing); Homologous transplantation; Immunology; Inflammation; Inflammation - metabolism; Inflammation - prevention & control; Interleukin-10 - blood; Interleukin-10 - genetics; Interleukin-10 - metabolism; Intramuscular injections; Isogeneic transplantation; Oxygenases - metabolism; Protective effects; Rats; T lymphocytes; Transgenes - genetics; Transplantation; Transplantation, Homologous; Vascular grafting
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0502407102

Interleukin 10 (IL-10) is a pleiotropic cytokine with well known antiinflammatory, immunosuppressive, and immunostimulatory properties. Chronic allograft rejection, characterized by vascular neointimal proliferation, is a major cause of organ transplant loss, particularly in heart and kidney transplant recipients. In a Dark Agouti to Lewis rat model of aortic transplantation, we evaluated the effects of a single intramuscular injection of a recombinant adeno-associated viral vector (serotype 1) encoding IL-10 (rAAV1-IL-10) on neointimal proliferation and inflammation. rAAV1-IL-10 treatment resulted in a significant reduction of neointimal proliferation and graft infiltration with macrophages and T and B lymphocytes. The mechanism underlying the protective effects of IL-10 in aortic allografts involved heme oxygenase 1 (HO-1) because inhibition of HO activity reversed not only neointimal proliferation but also inflammatory cell infiltration. Our results indicate that IL-10 attenuates neointimal proliferation and inflammatory infiltration and strongly imply that HO-1 is an important intermediary through which IL-10 regulates the inflammatory responses associated with chronic vascular rejection.