?-Linoleic acid enhances the capacity of ?-1 antitrypsin to inhibit lipopolysaccharide-induced IL-1? in human blood neutrophils.

ABSTRACT: Alpha1-antitrypsin (A1AT, SERPINA1), a major circulating inhibitor of neutrophil elastase (NE) and proteinase-3 (PRN3), has been proposed to reduce the processing and release of IL-1?. Since the anti-inflammatory properties of A1AT are influenced by the presence of polyunsaturated fatty acids, we compared effects of fatty acid-free (A1AT-0) and ?-linoleic acid-bound (A1AT-LA) forms of A1AT on lipopolysaccharide (LPS)-induced synthesis of IL-1? precursor and the release of IL-1? from human blood neutrophils. The presence of A1AT-LA or A1AT-0 significantly reduced LPS-induced release of mature IL-1?. However, only A1A-LA reduced both steady state mRNA levels of IL-1? and the secretion of mature IL-1?. In LPS stimulated neutrophils, mRNA levels of TLR2/4, NFKBIA, P2RX7, NLRP3, and CASP1 decreased significantly in the presence of A1AT-LA but not A1AT-0. A1AT-0 and A1AT-LA did not inhibit the direct enzymatic activity of caspase-1, but we observed complexes of either form of A1AT with NE and PR3. Consistent with the effect on TLR and IL-1? gene expression, only A1AT-LA inhibited LPS-induced gene expression of NE and PR3. Increased gene expression of PPAR-? was observed in A1AT-LA-treated neutrophils without of LPS stimulation, and the selective PPAR-? antagonist (GW9662) prevented the reduction in IL-1? by A1AT-LA. We conclude from our data, that the ability of A1AT to reduce TLR and IL-1? gene expression depends on its association with LA. Moreover, the anti-inflammatory properties of A1AT-LA are likely to be mediated by the activation of PPAR-?.

SUBMITTER: Aggarwal N 

PROVIDER: S-EPMC5135082 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other