Interplay of cysteinyl leukotrienes and TGF-β in the activation of hepatic stellate cells from Schistosoma mansoni granulomas |
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| Authors: | Ligia A Paiva Clarissa M Maya-Monteiro Christianne Bandeira-Melo Patricia MR Silva Marcia C El-Cheikh Anderson J Teodoro Radovan Borojevic Sandra AC Perez Patricia T Bozza |
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| Institution: | 1. Laboratory of Immunopharmacology, Institute Oswaldo Cruz, Manguinhos, Rio de Janeiro, RJ, Brazil;2. Laboratory of Inflammation, Institute Oswaldo Cruz, Manguinhos, Rio de Janeiro, RJ, Brazil;3. FarManguinhos, Fiocruz, Rio de Janeiro, RJ, Brazil;4. Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;5. Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;1. College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, China;2. Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, 600 Changjiang Road, Harbin 150030, China;1. Department of Surgery, University of Texas Medical Branch, Galveston, Texas;2. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas;3. Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas;1. Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av do Cafe s/n, Ribeirao Preto, SP, Brazil;2. Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Av dos Bandeirantes, 1900, Ribeirao Preto, SP, Brazil;1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;2. Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt |
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| Abstract: | Hepatic stellate cells (HSCs) have a critical role in liver physiology, and in the pathogenesis of liver inflammation and fibrosis. Here, we investigated the interplay between leukotrienes (LT) and TGF-β in the activation mechanisms of HSCs from schistosomal granulomas (GR-HSCs). First, we demonstrated that GR-HSCs express 5-lipoxygenase (5-LO), as detected by immunolocalization in whole cells and confirmed in cell lysates through western blotting and by mRNA expression through RT-PCR. Moreover, mRNA expression of 5-LO activating protein (FLAP) and LTC4-synthase was also documented, indicating that GR-HSCs have the molecular machinery required for LT synthesis. Morphological analysis of osmium and Oil-Red O-stained HSC revealed large numbers of small lipid droplets (also known as lipid bodies). We observed co-localization of lipid droplet protein marker (ADRP) and 5-LO by immunofluorescence microscopy. We demonstrated that GR-HSCs were able to spontaneously release cysteinyl-LTs (CysLTs), but not LTB4, into culture supernatants. CysLT production was highly enhanced after TGF-β-stimulation. Moreover, the 5-LO inhibitor zileuton and 5-LO gene deletion were able to inhibit the TGF-β-stimulated proliferation of GR-HSCs, suggesting a role for LTs in HSC activation. Here, we extend the immunoregulatory function of HSC by demonstrating that HSC from liver granulomas of schistosome-infected mouse are able to release Cys-LTs in a TGF-β-regulated manner, potentially impacting pathogenesis and liver fibrosis in schistosomiasis. |
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