15-ketoprostaglandin-e2 and Disease-Models--Animal

Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.

Topics: Animals; Animals, Genetically Modified; Cell Culture Techniques; Cryptococcosis; Cryptococcus neoformans; Dinoprostone; Disease Models, Animal; Eicosanoids; Host-Pathogen Interactions; Humans; Macrophages; PPAR gamma; Virulence; Zebrafish

Overproduction of prostaglandin E

Topics: Animals; Biomarkers; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromatography, Liquid; Dinoprostone; Disease Models, Animal; Disease Progression; Female; Humans; Mice; Phosphorylation; Protein Binding; Proteomics; Signal Transduction; STAT3 Transcription Factor; Structure-Activity Relationship; Tandem Mass Spectrometry; Xenograft Model Antitumor Assays

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.

Topics: Animals; Bicarbonates; Carbonic Anhydrase II; Carbonic Anhydrase IV; Colon; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dinoprostone; Disease Models, Animal; Female; Gene Expression; Hypoglycemic Agents; Male; Mice; Mice, Inbred CFTR; PPAR gamma; Rosiglitazone; Signal Transduction; Thiazolidinediones

Topics: Animals; Carbonic Anhydrase II; Carbonic Anhydrase IV; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dinoprostone; Disease Models, Animal; Humans; Hypoglycemic Agents; Mice; Mice, Inbred CFTR; Mucus; PPAR gamma; Rosiglitazone; Thiazolidinediones