title: HLA class I molecules partner with integrin β4 to stimulate endothelial cell proliferation and migration.
abstract: Among transplant recipients, those who produce antibodies against the donor's human leukocyte antigens (HLAs) are at higher risk for antibody-mediated rejection and transplant vasculopathy, which is a progressive, vasculo-occlusive disease that results in ischemic injury and deterioration of organ function. Antibodies against HLA class I (HLA-I) molecules are thought to contribute to transplant vasculopathy by triggering signals that elicit the activation and proliferation of endothelial cells. Here, we demonstrate a molecular association between HLA-I and the integrin β(4) subunit after the stimulation of endothelial cells with HLA-I-specific antibodies. Knockdown of integrin β(4) in these cells abrogated the ability of HLA-I to stimulate the phosphorylation of the kinases Akt, extracellular signal-regulated kinase (ERK), and Src, as well as cellular proliferation. Similarly, reducing the abundance of HLA-I suppressed integrin β(4)-mediated phosphorylation of ERK and the migration of endothelial cells on laminin-5, a component of the extracellular matrix. These results indicate a mutual dependency between HLA-I and the integrin β(4) subunit to stimulate the proliferation and migration of endothelial cells, which may be important in promoting transplant vasculopathy and tumor angiogenesis.
authors.affiliation: Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Zhang
authors.forename: Enrique
authors.initials: E
authors.lastname: Rozengurt
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Reed
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection; D014945:Wound Healing / Q000235:genetics / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D048049:Extracellular Signal-Regulated MAP Kinases; D015395:Histocompatibility Antigens Class I; D039663:Integrin beta4; D051058:Oncogene Protein v-akt; D034741:RNA, Small Interfering; D019061:src-Family Kinases; D000097794:Kalinin