20‐Hydroxy‐ and 20‐carboxy‐leukotriene (LT) B4 downregulate LTB4‐mediated responses of human neutrophils and eosinophils

摘要

Leukotriene Bsub4/sub (LTBsub4/sub) plays a prominent role in innate immunity as it induces phagocyte recruitment, the release of antimicrobial effectors, and as it potentiates the ingestion and killing of pathogens. In humans, LTBsub4/sub has a short half‐life and is rapidly metabolized by leukocytes, notably into 20‐OH‐ and 20‐COOH‐LTBsub4/sub by neutrophils. Although these LTBsub4/sub metabolites bind to the BLTsub1/sub receptor with high affinity, they activate neutrophils to a much lower extent than LTBsub4/sub. We thus postulated that LTBsub4/sub metabolites could dampen BLTsub1/sub‐mediated responses, therefore limiting the impact of LTBsub4/sub on human neutrophil functions. We found that 20‐OH‐LTBsub4/sub and 20‐COOH‐LTBsub4/sub inhibited all of the LTBsub4/sub‐mediated neutrophil responses we tested (migration, degranulation, leukotriene biosynthesis). The potencies of the different compounds at inhibiting LTBsub4/sub‐mediated responses were 20‐OH‐LTBsub4/sub?=?CP 105,696 (BLTsub1/sub antagonist)???20‐COOH‐LTBsub4/sub ≥ resolvin Esub1/sub (RVEsub1/sub). In contrast, the fMLP‐ and IL‐8‐mediated responses we tested were not affected by the LTBsub4/sub metabolites or RVEsub1/sub. 20‐OH‐LTBsub4/sub and 20‐COOH‐LTBsub4/sub also inhibited the LTBsub4/sub‐mediated migration of human eosinophils but not that induced by 5‐KETE. Moreover, using 20‐COOH‐LTBsub4/sub, LTBsub4/sub, and LTBsub4/sub‐alkyne, we show that LTBsub4/sub is a chemotactic, rather than a chemokinetic factor for both human neutrophils and eosinophils. In conclusion, our data indicate that LTBsub4/sub metabolites and RVEsub1/sub act as natural inhibitors of LTBsub4/sub‐mediated responses. Thus, preventing LTBsub4/sub ω‐oxidation might result in increased innate immunity and granulocyte functions.