Aspirin-triggered lipoxin A4 attenuates LPS-induced pro-inflammatory responses by inhibiting activation of NF-κB and MAPKs in BV-2 microglial cells

Background: Microglial activation plays an important role in neurodegenerative diseases through production of nitric oxide (NO) and several pro-inflammatory cytokines. Lipoxins (LXs) and aspirin-triggered LXs (ATLs) are considered to act as 'braking signals' in inflammation. In the present study, we investigated the effect of aspirin-triggered LXA(4) (ATL) on infiammatory responses induced by lipopolysaccharide (LPS) in murine microglial BV-2 cells. Methods: BV-2 cells were treated with ATL prior to LPS exposure, and the effects of such treatment production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) were analysed by Griess reaction, ELISA, western blotting and quantitative RT-PCR. Moreover, we investigated the effects of ATL on LPS-induced nuclear factor-kappa B (NF-kappa B) activation, phosphorylation of mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) activation. Results: ATL inhibited LPS-induced production of NO, IL-1 beta and TNF-alpha in a concentration-dependent manner. mRNA expressions for iNOS, IL-1 beta and TNF-alpha in response to LPS were also decreased by ATL. These effects were inhibited by Boc-2 (a LXA(4) receptor antagonist). ATL significantly reduced nuclear translocation of NF-kappa B p65, degradation of the inhibitor I kappa B-alpha, and phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK in BV-2 cells activated with LPS. Furthermore, the DNA binding activity of NF-kappa B and AP-1 was blocked by ATL. Conclusions: This study indicates that ATL inhibits NO and pro-inflammatory cytokine production at least in part via NF-kappa B, ERK, p38 MAPK and AP-1 signaling pathways in LPS-activated microglia. Therefore, ATL may have therapeutic potential for various neurodegenerative diseases.