title: Inhibition of human neutrophil chemotaxis by the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) piperazine.
abstract: The protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) piperazine (C-I), inhibits superoxide release from human neutrophils (PMN) stimulated with phorbol myristate acetate or synthetic diacylglycerol, without inhibiting superoxide release from PMN stimulated with the chemoattractants C5a or N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). In this study, we investigated the effect of C-I on human PMN chemotaxis to C5a, f-Met-Leu-Phe, leukotriene B4 (LTB4), and fluoresceinated N-formyl-methionyl-leucyl-phenylalanine-lysine (f-Met-Leu-Phe-Lys-FITC). PMN, preincubated for 5 min at 37 degrees C with 0 to 200 microM C-I, were tested for their migratory responses to the chemoattractants. C-I (greater than or equal to 1 microM) significantly inhibited PMN chemotaxis to f-Met-Leu-Phe, f-Met-Leu-Phe-Lys-FITC, and C5a without affecting random migration. Maximal inhibition of chemotaxis to these attractants occurred with greater than or equal to 50 microM C-I, at which chemotaxis was inhibited by 80 to 95%. The C-I inhibition was reversible. In contrast, 200 microM C-I did not inhibit the number of PMN migrating to LTB4, although, the leading front of PMN migration to LTB4 was inhibited by C-I. C-I inhibited PMN orientation to C5a and f-Met-Leu-Phe without affecting orientation to LTB4. C-I did not inhibit the binding of radiolabeled f-Met-Leu-Phe or f-Met-Leu-Phe-Lys-FITC to PMN. These findings suggest that the chemotactic responses of PMN to f-Met-Leu-Phe and C5a involve a protein kinase-dependent reaction which is inhibited by C-I.
authors.affiliation: Division of Blood and Blood Products, Food and Drug Administration, Bethesda, MD.
authors.forename: L
authors.initials: L
authors.lastname: Harvath
authors.forename: C E
authors.initials: CE
authors.lastname: McCall
authors.forename: D A
authors.initials: DA
authors.lastname: Bass
authors.forename: L C
authors.initials: LC
authors.lastname: McPhail
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003182:Complement C5 / Q000494:pharmacology; D015936:Complement C5a; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism
chemical_list: D003182:Complement C5; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; C052422:1-(5-isoquinolinesulfonyl)piperazine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine