Specific inhibition of leukotriene B4 (LTB4)‐induced neutrophil emigration by 20‐hydroxy LTB4: implications for the regulation of inflammatory responses

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Abstract
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.

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