Heparan sulfate proteoglycans are involved in opiate receptor-mediated cell migration.
Opioid receptors are expressed in cells of the immune system, and potent immunomodulatory effects of their natural and synthetic ligands have been reported. In some studies, the opiate receptor antagonist naloxone itself displayed immunomodulatory actions. We investigated effects of naloxone on leukocyte chemotaxis. Cell migration was tested in micropore filter assays using modified Boyden chambers, and receptor expression was investigated using radiolabel binding assays. Naloxone induced peripheral blood nonadherent mononuclear cell and neutrophil chemotaxis at nanomolar concentrations and deactivated their migration toward beta-endorphin, angiotensin II, somatostatin, or interleukin-8 but not toward RANTES, vasoactive intestinal peptide, or substance P. Ligand binding studies showed no alteration in the binding of interleukin-8 to neutrophils by naloxone. Cleavage of heparan sulfate from proteoglycans on the cells' surface completely inhibited chemotactic and deactivating properties of naloxone but not other attractants. Chemotactic properties were abolished by pretreating cells with heparinase, chondroitinase, sodium chlorate, and anti-syndecan-4 antibodies, indicating the involvement of syndecan-4. The extent of migration toward naloxone was diminished by pretreatment with dimethylsphingosine, a specific sphingosine kinase inhibitor. As syndecan-4 signaling in leukocyte chemotaxis involves activation of sphingosine kinase, results indicate that naloxone interacts with syndecan-4 function in cell migration and suggest a role for heparan sulfate proteoglycans as coreceptors to members of the delta-opiate receptor family.
Kaneider
Nicole C
NC
Division of General Internal Medicine, Department of Internal Medicine, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
Dunzendorfer
Stefan
S
Wiedermann
Christian J
CJ
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002464:Cell Migration Inhibition; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D002704:Chlorates / Q000494:pharmacology; D002810:Chondroitinases and Chondroitin Lyases / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology; D009270:Naloxone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D011509:Proteoglycans / Q000276:immunology / Q000502:physiology; D011957:Receptors, Opioid / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D053671:Syndecan-4; D000099157:Sphingosine Kinase
D000911:Antibodies, Monoclonal; D002704:Chlorates; D002810:Chondroitinases and Chondroitin Lyases; D019812:Heparan Sulfate Proteoglycans; D019763:Heparin Lyase; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D009270:Naloxone; D017853:Phosphotransferases (Alcohol Group Acceptor); D011509:Proteoglycans; D011957:Receptors, Opioid; D013110:Sphingosine; D053671:Syndecan-4; D000099157:Sphingosine Kinase; C508304:SDC4 protein, human; C061800:N,N-dimethylsphingosine; C032706:sodium chlorate