title: Carbon monoxide down-regulates α4β1 integrin-specific ligand binding and cell adhesion: a possible mechanism for cell mobilization.
abstract: BACKGROUND
  Carbon monoxide (CO), a byproduct of heme degradation, is attracting growing attention from the scientific community. At physiological concentrations, CO plays a role as a signal messenger that regulates a number of physiological processes. CO releasing molecules are under evaluation in preclinical models for the management of inflammation, sepsis, ischemia/reperfusion injury, and organ transplantation. Because of our discovery that nitric oxide signaling actively down-regulates integrin affinity and cell adhesion, and the similarity between nitric oxide and CO-dependent signaling, we studied the effects of CO on integrin signaling and cell adhesion.
  
  
  RESULTS
  We used a cell permeable CO releasing molecule (CORM-2) to elevate intracellular CO, and a fluorescent Very Late Antigen-4 (VLA-4, α4β1-integrin)-specific ligand to evaluate the integrin state in real-time on live cells. We show that the binding of the ligand can be rapidly down-modulated in resting cells and after inside-out activation through several Gαi-coupled receptors. Moreover, cell treatment with hemin, a natural source of CO, resulted in comparable VLA-4 ligand dissociation. Inhibition of VLA-4 ligand binding by CO had a dramatic effect on cell-cell interaction in a VLA-4/VCAM-1-dependent cell adhesion system.
  
  
  CONCLUSIONS
  We conclude that the CO signaling pathway can rapidly down-modulate binding of the VLA-4 -specific ligand. We propose that CO-regulated integrin deactivation provides a basis for modulation of immune cell adhesion as well as rapid cell mobilization, for example as shown for splenic monocytes in response to surgically induced ischemia of the myocardium.
authors.affiliation: Department of Pathology and University of New Mexico Cancer Center, Albuquerque 87131, NM, USA. achigaev@salud.unm.edu.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chigaev
authors.forename: Yelena
authors.initials: Y
authors.lastname: Smagley
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D009842:Oligopeptides / Q000378:metabolism; D010671:Phenylurea Compounds / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013379:Substrate Specificity / Q000187:drug effects; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C517048:4-((N'-2-methylphenyl)ureido)phenylalanyl-leucyl-alpha-aspartyl-valyl-prolyl-alanyl-alanyl-lysine; D039041:Integrin alpha4beta1; D008024:Ligands; D009842:Oligopeptides; D010671:Phenylurea Compounds; D021122:Protein Subunits; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; D019010:Vascular Cell Adhesion Molecule-1; D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D006162:Guanylate Cyclase; D006152:Cyclic GMP