Glucocorticoids co-interact with lipoxin A4 via lipoxin A4 receptor (ALX) up-regulation

Lipoxin A4 (LXA4) is an eicosanoid which is produced via lipoxygenases and characteristic of its anti-inflammatory effect in many metabolites of arachidonic acid, which are mostly pro-inflammatory. Glucocorticoids are well known also for their strong anti-inflammatory action but induce 5-lipoxygenase, essential to synthesize leukotrienes, which are pro-inflammatory. To elucidate the interaction of glucocorticoids and lipoxin A4 for anti-inflammation, we analyzed in vitro expression of lipoxin A4 receptor (ALX) on human neutrophils and the in vivo anti-inflammatory effect of glucocorticoids and LXA4 using a dermal inflammation mouse model. ALX mRNA was up-regulated by dexamethasone (Dex) in human neutrophils. A glucocorticoid receptor antagonist, mifepristone, suppressed up-regulation of ALX induced by Dex. LXA4 and/or Dex decreased CD11b expression on human neutrophils and suppressed mouse dermatitis induced by LTB4. These results suggest that anti-inflammatory effects of glucocorticoids depend at least partly on up-regulation of ALX and that the lipoxin system could be a negative feedback regulator for LTB4.