The opioid peptide dynorphin A induces leukocyte responses via integrin Mac-1 (aα<inf>M</inf>β<inf>2</inf>, CD11b/CD18)

Nataly Podolnikova, Julie A. Brothwell, Tatiana Ugarova

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 (aα<inf>M</inf>β<inf>2</inf>, 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 aα<inf>M</inf>I-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 aα<inf>M</inf>I-domain was activation independent as both the aα7 helix-truncated (active conformation) and helix-extended (nonactive conformation) aα<inf>M</inf>I-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.

Original languageEnglish (US)
Article number33
JournalMolecular Pain
Volume11
Issue number1
DOIs
StatePublished - Jun 3 2015

Fingerprint

Dynorphins
Opioid Peptides
Leukocytes
Ligands
leukocyte response integrin
Macrophages
Peptide Library
Proteoglycans
Microspheres
Phagocytosis
Integrins
Nervous System
Analgesics
Heparin
Monocytes
Immune System
Neutrophils
rimorphin

Keywords

  • Adhesion molecules
  • Dynorphin A
  • Integrin Mac-1 (CD11b/CD18)
  • Leukocytes
  • Opioid peptides

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Molecular Medicine
  • Cellular and Molecular Neuroscience

Cite this

@article{419f301381c044329e0607d37a3287d5,
title = "The opioid peptide dynorphin A induces leukocyte responses via integrin Mac-1 (aαMβ2, 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 (aαMβ2, 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 aαMI-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 aαMI-domain was activation independent as both the aα7 helix-truncated (active conformation) and helix-extended (nonactive conformation) aαMI-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.",
keywords = "Adhesion molecules, Dynorphin A, Integrin Mac-1 (CD11b/CD18), Leukocytes, Opioid peptides",
author = "Nataly Podolnikova and Brothwell, {Julie A.} and Tatiana Ugarova",
year = "2015",
month = "6",
day = "3",
doi = "10.1186/s12990-015-0027-0",
language = "English (US)",
volume = "11",
journal = "Molecular Pain",
issn = "1744-8069",
publisher = "BioMed Central",
number = "1",

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TY - JOUR

T1 - The opioid peptide dynorphin A induces leukocyte responses via integrin Mac-1 (aαMβ2, CD11b/CD18)

AU - Podolnikova, Nataly

AU - Brothwell, Julie A.

AU - Ugarova, Tatiana

PY - 2015/6/3

Y1 - 2015/6/3

N2 - 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 (aαMβ2, 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 aαMI-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 aαMI-domain was activation independent as both the aα7 helix-truncated (active conformation) and helix-extended (nonactive conformation) aαMI-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.

AB - 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 (aαMβ2, 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 aαMI-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 aαMI-domain was activation independent as both the aα7 helix-truncated (active conformation) and helix-extended (nonactive conformation) aαMI-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.

KW - Adhesion molecules

KW - Dynorphin A

KW - Integrin Mac-1 (CD11b/CD18)

KW - Leukocytes

KW - Opioid peptides

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U2 - 10.1186/s12990-015-0027-0

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SN - 1744-8069

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