title: The opioid peptide dynorphin A induces leukocyte responses via integrin Mac-1 (αMβ2, CD11b/CD18).
abstract: BACKGROUND
  Opioid peptides, including dynorphin A, besides their analgesic action in the nervous system, exert a broad spectrum of effects on cells of the immune system, including leukocyte migration, degranulation and cytokine production. The mechanisms whereby opioid peptides induce leukocyte responses are poorly understood. The integrin Mac-1 (αMβ2, CD11b/CD18) is a multiligand receptor which mediates numerous reactions of neutrophils and monocyte/macrophages during the immune-inflammatory response. Our recent elucidation of the ligand recognition specificity of Mac-1 suggested that dynorphin A and dynorphin B contain Mac-1 recognition motifs and can potentially interact with this receptor.
  
  
  RESULTS
  In this study, we have synthesized the peptide library spanning the sequence of dynorphin AB, containing dynorphin A and B, and showed that the peptides bound recombinant αMI-domain, the ligand binding region of Mac-1. In addition, immobilized dynorphins A and B supported adhesion of the Mac-1-expressing cells. In binding to dynorphins A and B, Mac-1 cooperated with cell surface proteoglycans since both anti-Mac-1 function-blocking reagents and heparin were required to block adhesion. Further focusing on dynorphin A, we showed that its interaction with the αMI-domain was activation independent as both the α7 helix-truncated (active conformation) and helix-extended (nonactive conformation) αMI-domains efficiently bound dynorphin A. Dynorphin A induced a potent migratory response of Mac-1-expressing, but not Mac-1-deficient leukocytes, and enhanced Mac-1-mediated phagocytosis of latex beads by murine IC-21 macrophages.
  
  
  CONCLUSIONS
  Together, the results identify dynorphins A and B as novel ligands for Mac-1 and suggest a role for the Dynorphin A-Mac-1 interactions in the induction of nonopiod receptor-dependent effects in leukocytes.
authors.affiliation: From the Center for Metabolic and Vascular Biology, School of Life Sciences, Arizona State University, Tempe, AZ, 85287, USA. Nataly.Podolnikova@asu.edu.
authors.forename: Nataly P
authors.initials: NP
authors.lastname: Podolnikova
authors.affiliation: From the Center for Metabolic and Vascular Biology, School of Life Sciences, Arizona State University, Tempe, AZ, 85287, USA. jbrothwe@umail.iu.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Brothwell
authors.affiliation: From the Center for Metabolic and Vascular Biology, School of Life Sciences, Arizona State University, Tempe, AZ, 85287, USA. Tatiana.Ugarova@asu.edu.
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Ugarova
mesh_terms: D000595:Amino Acid Sequence; D002448:Cell Adhesion / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004399:Dynorphins / Q000737:chemistry / Q000494:pharmacology*; D004723:Endorphins / Q000737:chemistry / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008863:Microspheres; D008969:Molecular Sequence Data; D019151:Peptide Library; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012995:Solubility; D020298:U937 Cells
chemical_list: D004723:Endorphins; D008024:Ligands; D016177:Macrophage-1 Antigen; D019151:Peptide Library; D004399:Dynorphins; C036200:rimorphin; D005340:Fibrinogen