Selectin-mediated interactions regulate cytokine networks and macrophage heme oxygenase-1 induction in cardiac...

Host sensitization to major histocompatibility complex (MHC) antigens is among the most critical of problems facing heart transplantation. Selectins are postulated to mediate the early adhesive events in the recruitment of leukocytes at the allograft site. We investigated the significance of selectin-P-selectin glycoprotein ligand-1 (PSGL-1)-mediated in vivo interactions in the immune cascade leading to rejection of cardiac allografts in skin presensitized rats. Infusion of a soluble recombinant form of PSGL-1 (rPSGL-Ig) during skin graft-mediated sensitization prevented Day 1.0 +/- 0.1 "accelerated" rejection in sensitized rat recipients, and prolonged cardiac allograft survival to Day 3.8 +/- 1.0 (p < 0.001). This therapy significantly depressed serum IgM levels and decreased intragraft expression of Th1 type cytokines (IL-2 and IFN-gamma) as well as of IL-1beta and MCP-1, as compared with controls, without affecting the initial number of infiltrating mononuclear cells (MNC). A profound decrease in graft-infiltrating MNC was recorded at 24 hours in rPSGL-Ig-treated rats. The expression of heme oxygenase-1 (HO-1), an inducible heat shock protein 32 that protects against oxidative cell/tissue injury, was found in approximately 14-fold higher levels in the rPSGL-Ig-treated recipients as compared with controls. The HO-1 overexpression in rPSGL-Ig-treated hosts, primarily by infiltrating macrophages, was accompanied by virtual absence of myocardial infarcts and decreased frequency of TUNEL + cells at the graft site. Moreover, down-regulation of HO-1 expression by zinc protoporphyrin, an HO-1 antagonist, decreased expression of antiapoptotic Bag-1 molecule in recipients conditioned with rPSGL-Ig. Thus, the blockade of selectin-PSGL-1 interactions depresses intracardiac allograft expression of Th1 type cytokines, and might inhibit the differentiation of Th1 type cells. In addition, it up-regulates HO-1 expression and protects against myocardial infarction and apoptosis. Hence, this study reports on a previously unrecognized role of selectin-PSGL-1-mediated interactions after in vivo alloantigenic challenge.