title: Schistosome infection-derived Hepatic Stellate Cells are cellular source of prostaglandin D₂: role in TGF-β-stimulated VEGF production.
abstract: Hepatic Stellate Cells (HSCs) play a crucial role in pathogenesis of liver inflammation and fibrosis. During chronic liver injury, HSCs lose vitamin A and transform into myofibroblastic cells. In schistosomal granulomas, these activated HSCs are called GR-HSCs. Schistosomal-triggered hepatic fibrogenesis has TGF-β as the most potent fibrogenic stimulus, that also controls gene expression of the angiogenic molecule VEGF in HSCs. COX-dependent production of prostaglandins (PGs) also play role in angiogenic processes. Besides angiogenic roles, prostanoids control immunomodulation of Schistosoma mansoni infection. Specifically, schistosoma-derived PGD2 has emerged as a key parasite regulator of immune defense evasion, while no role is still established to host PGD2. Therefore, the aim of this work is to investigate the ability of GR-HSCs to synthesize COX-derived PGD2 and a potential role of this prostanoid in VEGF production by GR-HSCs in vitro. Here, we confirmed that GR-HSCs express COX-2, which displayed perinuclear localization. While unstimulated GR-HSCs produce basal levels of PGD2, TGF-β stimulation besides increasing COX2- mRNA levels, enhanced synthesis/secretion of PGD2 in GR-HSCs supernatant. Moreover, GR-HSCs-derived PGD2 mediate VEGF production by TGF-β-stimulated GR-HSCs, since the pre-treatment with HQL-79, an inhibitor of hematopoietic PGD synthase inhibited both PGD2 synthesis and VEGF secretion by TGF-β-stimulated GR-HSCs. All together, our findings show an autocrine/paracrine activity of GR-HSCs-derived PGD2 on TGF-β-induced VEGF production by GR-HSCs, unveiling a role for PGD2 as important regulator of HSCs activation in hepatic granulomas from schistosome infected mice.
authors: Laboratory of Immunopharmacology, FIOCRUZ, RJ, Brazil. Electronic address: ligia@ioc.fiocruz.br.
authors: Ligia Almeida
authors: LA
authors: Paiva
authors: Laboratory of Immunopharmacology, FIOCRUZ, RJ, Brazil.
authors: Karen Almeida
authors: KA
authors: Coelho
authors: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, RJ, Brazil.
authors: Tatiana
authors: T
authors: Luna-Gomes
authors: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, RJ, Brazil.
authors: Marcia Cury
authors: MC
authors: El-Cheikh
authors: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, RJ, Brazil.
authors: Radovan
authors: R
authors: Borojevic
authors: Farmanguinhos, FIOCRUZ, RJ, Brazil.
authors: Sandra Aurora
authors: SA
authors: Perez
authors: Laboratory of Immunopharmacology, FIOCRUZ, RJ, Brazil.
authors: Patricia Torres
authors: PT
authors: Bozza
authors: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, RJ, Brazil. Electronic address: cbmelo@biof.ufrj.br.
authors: Christianne
authors: C
authors: Bandeira-Melo
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D006099:Granuloma / Q000201:enzymology / Q000378:metabolism* / Q000469:parasitology; D055166:Hepatic Stellate Cells / Q000201:enzymology / Q000378:metabolism / Q000469:parasitology*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000378:metabolism*; D012555:Schistosomiasis mansoni / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C116322:4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine; D010880:Piperidines; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2
keywords: Eosinophil; Hepatic Stellate Cells; Prostaglandin D(2); S. mansoni; VEGF