title: Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection.
abstract: FLI1 (Friend leukemia virus integration 1) and IL6 (interleukin 6; IL-6) are associated with Leishmania braziliensis susceptibility. Cutaneous lesions show exaggerated matrix metalloproteinase 1 (MMP1). In other skin diseases, FLI1 promoter methylation reduces FLI1 expression, and low FLI1 down-regulates MMP1. IL-6 increases FLI1 expression. We hypothesized that epigenetic regulation of FLI1 in cutaneous leishmaniasis, together with IL-6, might determine MMP1 expression. While generally low (<10%), percent FLI1 promoter methylation was lower (P=0.001) in lesion biopsies than normal skin. Contrary to expectation, a strong positive correlation occurred between FLI1 methylation and gene expression in lesions (r=0.98, P=0.0005) and in IL-6-treated L. braziliensis-infected macrophages (r=0.99, P=0.0004). In silico analysis of the FLI1 promoter revealed co-occurring active H3K27ac and repressive DNA methylation marks to enhance gene expression. FLI1 expression was enhanced between 3 and 24hour post infection in untreated (P=0.0002) and IL-6-treated (P=0.028) macrophages. MMP1 was enhanced in lesion biopsies (P=0.0002), induced (P=0.007) in infected macrophages, but strongly inhibited by IL-6. No correlations occurred between FLI1 and MMP1 expression in lesions or infected macrophages (with/without IL-6). We conclude that MMP1 is regulated by factors other than FLI1, and that the influence of IL-6 on MMP1 was independent of its effect on FLI1.
authors.affiliation: National Institute of Cience and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.|Program of Post-graduation in Health Sciences, Federal University of Bahia, Salvador, Brazil.
authors.forename: Lucas
authors.initials: L
authors.lastname: Almeida
authors.affiliation: National Institute of Cience and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.|Program of Post-graduation in Health Sciences, Federal University of Bahia, Salvador, Brazil.
authors.forename: Juliana A
authors.initials: JA
authors.lastname: Silva
authors.affiliation: National Institute of Cience and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.|Program of Post-graduation in Health Sciences, Federal University of Bahia, Salvador, Brazil.
authors.forename: Viviane M
authors.initials: VM
authors.lastname: Andrade
authors.affiliation: National Institute of Cience and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.
authors.forename: Paulo
authors.initials: P
authors.lastname: Machado
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, Australia.
authors.forename: Sarra E
authors.initials: SE
authors.lastname: Jamieson
authors.affiliation: National Institute of Cience and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Carvalho
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, Australia.|Department of Pathology and Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
authors.affiliation: National Institute of Cience and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.
authors.forename: Léa C
authors.initials: LC
authors.lastname: Castellucci
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology; D007892:Leishmania braziliensis / Q000472:pathogenicity / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000276:immunology; D011401:Promoter Regions, Genetic; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology
chemical_list: C078433:FLI1 protein, human; D006657:Histones; C508600:IL6 protein, human; D015850:Interleukin-6; D051789:Proto-Oncogene Protein c-fli-1; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Cutaneous lesions; FLI1; IL-6; Leishmaniasis; MMP1; Macrophages