Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection

Lucas Almeida, Juliana A. Silva, Viviane M. Andrade, Paulo Machado, Sarra E. Jamieson, Edgar M. Carvalho, Jenefer M. Blackwell, Léa C. Castellucci

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3 Citations (Scopus)

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 24 hour 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.

Original languageEnglish
Pages (from-to)212-220
Number of pages9
JournalInfection, Genetics and Evolution
Volume49
DOIs
Publication statusPublished - 1 Apr 2017

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Leishmania braziliensis
leishmaniasis
Friend murine leukemia virus
Virus Integration
interstitial collagenase
cutaneous leishmaniasis
Matrix Metalloproteinase 1
Cutaneous Leishmaniasis
leukemia
virus
Leukemia
interleukin-6
viruses
matrix
Interleukin-6
Infection
infection
lesion
methylation
lesions (animal)

Cite this

Almeida, Lucas ; Silva, Juliana A. ; Andrade, Viviane M. ; Machado, Paulo ; Jamieson, Sarra E. ; Carvalho, Edgar M. ; Blackwell, Jenefer M. ; Castellucci, Léa C. / Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection. In: Infection, Genetics and Evolution. 2017 ; Vol. 49. pp. 212-220.
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Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection. / Almeida, Lucas; Silva, Juliana A.; Andrade, Viviane M.; Machado, Paulo; Jamieson, Sarra E.; Carvalho, Edgar M.; Blackwell, Jenefer M.; Castellucci, Léa C.

In: Infection, Genetics and Evolution, Vol. 49, 01.04.2017, p. 212-220.

Research output: Contribution to journalArticle

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T1 - Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection

AU - Almeida, Lucas

AU - Silva, Juliana A.

AU - Andrade, Viviane M.

AU - Machado, Paulo

AU - Jamieson, Sarra E.

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AU - Blackwell, Jenefer M.

AU - Castellucci, Léa C.

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AB - 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 24 hour 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.

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