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 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.


CONCLUSIONS
Impaired regulation of nuclear receptors may contribute to the abnormal LPS induced signaling in CF macrophages and is reversed by DHA.
Andersson
Charlotte
C
Department of Medicine, Beth Israel Deaconess Medical Center, Boston 02215, MA, United States.
Zaman
Munir M
MM
Jones
Amanda B
AB
Freedman
Steven D
SD
D000818:Animals; D003550:Cystic Fibrosis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D004281:Docosahexaenoic Acids