Macrophage migration inhibitory factor counter‐regulates dexamethasone‐induced annexin 1 expression and influences the release of eicosanoids in murine macrophages

Macrophage migration inhibitory factor (MIF), a pro‐inflammatory cytokine and glucocorticoid (GC) counter‐regulator, has emerged as an important modulator of inflammatory responses. However, the molecular mechanisms of MIF counter‐regulation of GC still remain incomplete. In the present study, we investigated whether MIF mediated the counter‐regulation of the anti‐inflammatory effect of GC by affecting annexin 1 in RAW 264.7 macrophages. We found that stimulation of RAW 264.7 macrophages with lipopolysaccharide (LPS) resulted in down‐regulation of annexin 1, while GC dexamethasone (Dex) or Dex plus LPS led to significant up‐regulation of annexin 1 expression. RNA interference‐mediated knockdown of intracellular MIF increased annexin 1 expression with or without incubation of Dex, whereas Dex‐induced annexin 1 expression was counter‐regulated by the exogenous application of recombinant MIF. Moreover, recombinant MIF counter‐regulated, in a dose‐dependent manner, inhibition of cytosolic phospholipase A2α (cPLA2α) activation and prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄) release by Dex in RAW 264.7 macrophages stimulated with LPS. Endogenous depletion of MIF enhanced the effects of Dex, reflected by further decease of cPLA2α expression and lower PGE₂ and LTB₄ release in RAW 264.7 macrophages. Based on these data, we suggest that MIF counter‐regulates Dex‐induced annexin 1 expression, further influencing the activation of cPLA2α and the release of eicosanoids. These findings will add new insights into the mechanisms of MIF counter‐regulation of GC.