SPECIFIC-INHIBITION OF LEUKOTRIENE B(4) (LTB4)-INDUCED NEUTROPHIL EMIGRATION BY 20-HYDROXY LTB(4) - IMPLICATIONS FOR THE REGULATION OF INFLAMMATORY RESPONSES

1 The interaction between leukotriene B4 (LTB4) and its metabolite, 20-hydroxy 2 Leukotriene B4(10-300 ng) elicited a dose-dependent increase in neutrophil infiltration (as measured by myeloperoxidase activity) 4 h after injection into guinea-pig skin. In contrast, 20-hydroxy LTB4 (30-1000 ng) displayed only weak inflammatory activity in this assay. 3 Although 20-hydroxy LTB4 had low agonist activity, this metabolite caused a potent dose-dependent inhibition of responses to LTB4 (100 ng), when administered systemically (ED50 = 1.3 mug kg-1, s.c.) without significantly affecting neutrophil infiltration in response to C5a (2 mug). Systemic administration of 20-carboxy LTB4 (10 mug) did not affect neutrophil accumulation in response to LTB4 or C5a. In addition, neither 15(S)-hydroxy 5(S)-HPETE(10 mug) nor lipoxin A4 (10 mug) inhibited responses to LTB4. 4 Addition of 20-hydroxy LTB4 (10(-11)-10(-8) M) to human blood prior to isolation of the neutrophils led to concentration-dependent decrease in the number of LTB4 receptors and decreased chemotactic responsiveness to LTB4 without affecting responses to C5a. Incubation of blood with 20-carboxy LTB4 (10(-8) M) did not reduce LTB4 receptor number of chemotactic responsivness to LTB4. 5 These data indicate that although 20-hydroxy LTB4 is a weak agonist at LTB4 receptors, it can desensitize neutrophils to the effects of LTB4 via down-regulation of the high affinity receptor and thus provides evidence for a mechanism whereby inflammatory responses may be regulated.