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

Leukotriene B₄ (LTB₄ ) 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, LTB₄ has a short half-life and is rapidly metabolized by leukocytes, notably into 20-OH- and 20-COOH-LTB₄ by neutrophils. Although these LTB₄ metabolites bind to the BLT₁ receptor with high affinity, they activate neutrophils to a much lower extent than LTB₄ . We thus postulated that LTB₄ metabolites could dampen BLT₁ -mediated responses, therefore limiting the impact of LTB₄ on human neutrophil functions. We found that 20-OH-LTB₄ and 20-COOH-LTB₄ inhibited all of the LTB₄ -mediated neutrophil responses we tested (migration, degranulation, leukotriene biosynthesis). The potencies of the different compounds at inhibiting LTB₄ -mediated responses were 20-OH-LTB₄ = CP 105,696 (BLT₁ antagonist) > > 20-COOH-LTB₄ ≥ resolvin E₁ (RVE₁ ). In contrast, the fMLP- and IL-8-mediated responses we tested were not affected by the LTB₄ metabolites or RVE₁ . 20-OH-LTB₄ and 20-COOH-LTB₄ also inhibited the LTB₄ -mediated migration of human eosinophils but not that induced by 5-KETE. Moreover, using 20-COOH-LTB₄ , LTB₄ , and LTB₄ -alkyne, we show that LTB₄ is a chemotactic, rather than a chemokinetic factor for both human neutrophils and eosinophils. In conclusion, our data indicate that LTB₄ metabolites and RVE₁ act as natural inhibitors of LTB₄ -mediated responses. Thus, preventing LTB₄ ω-oxidation might result in increased innate immunity and granulocyte functions.

5-oxo-ETE; eosinophils; host defense; leukotriene B4; lipoxin A4; neutrophils; resolvin E1.