title: Selectin-mediated interactions regulate cytokine networks and macrophage heme oxygenase-1 induction in cardiac allograft recipients.
abstract: 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.
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, UCLA School of Medicine, Los Angeles, CA 90095, USA. acoito@mednet.ucla.edu
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Coito
authors.forename: Gray D
authors.initials: GD
authors.lastname: Shaw
authors.forename: Jiye
authors.initials: J
authors.lastname: Li
authors.forename: Bibo
authors.initials: B
authors.lastname: Ke
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ma
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics; D004790:Enzyme Induction; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D007165:Immunosuppression Therapy / Q000379:methods; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000201:enzymology*; D008285:Major Histocompatibility Complex; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D008565:Membrane Proteins; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000627:therapeutic use; D016038:Skin Transplantation / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C084882:P-selectin ligand protein; D011994:Recombinant Proteins; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1