Specific inhibition of leukotriene B4 (LTB4)‐induced neutrophil emigration by 20‐hydroxy LTB4: 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 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 μg kg−1, s.c.) without significantly affecting neutrophil infiltration in response to C5a (2 μg). Systemic administration of 20‐carboxy LTB4 (10 μg) did not affect neutrophil accumulation in response to LTB4 or C5a. In addition, neither 15(S)‐hydroxy 5(S)‐HPETE(10 μg) nor lipoxin A4 (10 μg) 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.