Alterations in immune response and PPAR/LXR regulation in cystic fibrosis macrophages.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is characterized by an excessive inflammatory response in epithelial cells and macrophages. In CF mice, lung inflammation can be abrogated by oral treatment with docosahexaenoic acid (DHA). Since PPARs and LXRs are important regulators of inflammation and fatty acid metabolism in macrophages, we hypothesized that these pathways are dysregulated in CF macrophages and are corrected with DHA treatment. METHODS: Peritoneal macrophages were obtained from wild type and cftr(-/-) mice. LPS induced cytokine secretion and NFkappaB activity were analyzed with and without oral DHA treatment. The expression and activity of PPARalpha,gamma, delta and LXRalpha were analyzed by RT-PCR and EMSA. RESULTS: LPS induced TNFalpha and IL-6 secretion and NFkappaB p65 activity were increased in CF macrophages. This was associated with low basal PPARgamma expression and attenuated LPS induced induction of PPARdelta, LXRalpha and ABCA1. DHA pretreatment in vivo decreased TNFalpha secretion and p65 activity, and increased PPARalpha and gamma expression and function. The effects of DHA could be reproduced by PPAR agonists and blocked by a PPARalpha antagonist. CONCLUSION: Impaired regulation of nuclear receptors may contribute to the abnormal LPS induced signaling in CF macrophages and is reversed by DHA.