Cyclical binding, processing, and functional interactions of neutrophils with leukotriene B4.
Leukotriene (LT) B4 activates human polymorphonuclear neutrophils (PMN) by binding to plasmalemmal receptors. It stimulates PMN to raise cytosolic calcium and degranulate. Both responses end within 15-30 sec. However, in less than 15 sec, LTB4-treated PMN lose the ability to respond further to LTB4; decrease the affinity and number of high affinity receptors available for binding LTB4; sequester LTB4 in plasmalemma-associated sites that are inaccessible to a releasing buffer regimen; and begin internalizing LTB4. Over the next 90 min, the cells increasingly internalize LTB4 and convert it to less potent metabolites; release the metabolites; recover LTB4 binding sites; and become fully sensitive to LTB4. Contrastingly, during the entire 90 min incubation with LTB4. PMN retained the capacity to bind and respond normally to a second stimulus, platelet-activating factor. We therefore suggest the following model. LTB4 receptors, when ligand-bound, initiate function but rapidly lose this capacity as they lower their ligand binding affinity and sequester, internalize, or otherwise uncouple from transducing elements. These LTB4 receptor changes contribute to terminating PMN responses and producing a stimulus-selective state of desensitization. During the desensitization period, PMN progressively process and metabolize LTB4. This removes LTB4 from the environment, thereby allowing PMN to recover functional receptors for and sensitivity to the ligand.
O'Flaherty
J T
JT
Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27103.
Redman
J F
JF
Jacobson
D P
DP
D002118:Calcium / Q000097:blood; D002462:Cell Membrane / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000201:enzymology; D005966:Glucuronidase / Q000097:blood; D006801:Humans; D007700:Kinetics; D007975:Leukotriene B4 / Q000097:blood* / Q000494:pharmacology; D009113:Muramidase / Q000097:blood; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D018102:Receptors, Leukotriene B4
D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D003571:Cytochalasin B; D009113:Muramidase; D005966:Glucuronidase; D002118:Calcium