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

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 NF kappa B activity were analyzed with and without oral DHA treatment. The expression and activity of PPAR alpha,gamma,delta and LXR alpha were analyzed by RT-PCR and EMSA. Results: LPS induced TNF alpha and IL-6 secretion and NF kappa B p65 activity were increased in CF macrophages. This was associated with low basal PPAR gamma expression and attenuated LPS induced induction of PPAR delta, LXR alpha and ABCA1 DHA pretreatment in vivo decreased TNFa secretion and p65 activity, and increased PPAR alpha and gamma expression and function. The effects of DHA could be reproduced by PPAR agonists and blocked by a PPARa antagonist. Conclusion: Impaired regulation of nuclear receptors may contribute to the abnormal LPS induced signaling in CF macrophages and is reversed by DHA. (C) 2007 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.