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 LTB4 in the control of neutrophil emigration was examined in guinea-pig skin.2 Leukotriene B4(10-300 ng) elicited a dose-dependent increase in neutrophil infiltration (as measured by myeloperoxidase ac tivity) 4 h after injection into guinea-pig skin. In contrast, 20-hydr oxy LTB4 (30-1000 ng) displayed only weak inflammatory activity in thi s assay. 3 Although 20-hydroxy LTB4 had low agonist activity, this met abolite 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 addi tion, 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)-1 0(-8) M) to human blood prior to isolation of the neutrophils led to c oncentration-dependent decrease in the number of LTB4 receptors and de creased chemotactic responsiveness to LTB4 without affecting responses to C5a. Incubation of blood with 20-carboxy LTB4 (10(-8) M) did not r educe LTB4 receptor number of chemotactic responsivness to LTB4. 5 The se data indicate that although 20-hydroxy LTB4 is a weak agonist at LT B4 receptors, it can desensitize neutrophils to the effects of LTB4 vi a down-regulation of the high affinity receptor and thus provides evid ence for a mechanism whereby inflammatory responses may be regulated.