RESUMO
Tuberculosis (TB) is an infectious disease displaying a multifactorial pathology. The immunomodulatory role attributed to steroid hormones, such as vitamin D3 (VD3) and 17ß-estradiol (E2), highlighted the importance of these hormones against Mycobacterium tuberculosis (Mtb) infection. In order to understand their influence upon gene expression of immune and inflammatory responsive genes against Mtb we tested it in vitro using peripheral blood mononuclear cells (PBMCs). Cells were pretreated with VD3 (50 ng/mL) or E2 (100 nM/mL) and co-cultured with H37Rv Mtb or stimulated with lipopolysaccharide from Escherichia coli (LPS). After 24 h and 72 h of co-culture the Mtb viability in macrophages test was performed, as well the total RNA isolation for gene expression analysis by RT-qPCR of the following target genes: NLRP3, DC-SIGN, IL-1ß, and IL-10. We also measured IL-10, TNF, IFN-γ, IL-4, IL-6, and IL-2 supernatant levels. As the main results, we found that VD3 and E2 downregulated the expression of inflammatory genes NLRP3, IL-1ß, and IL-10 expression in Mtb co-cultured cells. Finally, VD3 treatment increased the release of the cytokine IFN-γ in Mtb-infected cells, while E2 treatment inhibited the release of IL-10, TNF, IFN-γ, and IL-6. Therefore, we report an immunogenetic influence of VD3 and E2 upon Mtb co-culture.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Interleucina-10/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Leucócitos Mononucleares/metabolismo , Interleucina-6/metabolismo , Tuberculose/microbiologia , Colecalciferol , Hormônios/metabolismoRESUMO
The role of steroid hormones against infectious diseases has been extensively studied. From immunomodulatory action to direct inhibition of microorganism growth, hormones D3 (VD3) and 17ß-estradiol (E2), and the genetic pathways modulated by them, are key targets for a better understanding pathogenesis of infectious respiratory diseases (IRD) such as tuberculosis (TB) and the coronavirus disease-19 (COVID-19). Currently, the world faces two major public health problems, the outbreak of COVID-19, accounting for more than 6 million so far, and TB, more than 1 million deaths per year. Both, although resulting from different pathogens, the Mtb and the SARS-CoV-2, respectively, are considered serious and epidemic. TB and COVID-19 present similar infection rates between men and women, however the number of complications and deaths resulting from the two infections is higher in men when compared to women in childbearing age, which may indicate a role of the sex hormone E2 in the context of these diseases. E2 and VD3 act upon key gene pathways as important immunomodulatory players and supporting molecules in IRDs. This review summarizes the main roles of these hormones (VD3 and E2) in modulating immune and inflammatory responses and their relationship with TB and COVID-19.
RESUMO
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder that displays an important genetic background. Vitamin D3 (VD3 ) through its receptor (VDR) plays an important immunomodulatory role in autoimmune misbalance, being capable of modulating immune responses. Genetic alterations in VDR gene may contribute to an altered risk in SLE development and clinical manifestations. We investigated VDR SNPs (single nucleotide polymorphisms) frequencies in 128 SLE patients and 138 healthy controls (HC) and mRNA differential expression in 29 patients and 17 HC regarding SLE susceptibility as well as clinical features. We observed that rs11168268 G allele (OR = 1.55, p = .01) and G/G genotype (OR = 2.69, p = .008) were associated with increased SLE susceptibility. The rs2248098 G allele and A/G and G/G genotypes were associated to lower SLE susceptibility (OR = 0.66, p = .01; OR = 0.46, p = .01; OR = 0.44, p = .02, respectively). Regarding clinical features, we observed lower risk for: rs11168268 A/G genotype and nephritis (OR = 0.31, p = .01); rs4760648 T/T genotype and photosensitivity (OR = 0.24, p = .02); rs1540339 T/T genotype and antibody anti-dsDNA (OR = 0.19, p = .015); rs3890733 T/T genotype and serositis (OR = 0.10, p = .01). We identified a significant downregulation in VDR expression levels when compared patients and controls overall (p = 1.04e-7 ), in Cdx-2 A/G and G/G (p = .008 and p = .014, respectively) and in patients with nephritis (p = .016) Our results suggested that VDR SNPs influence upon SLE susceptibility and in particular clinical features, acting on mRNA expression in SLE patients overall and the ones with nephritis.
Assuntos
Lúpus Eritematoso Sistêmico , Nefrite , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/genética , Nefrite/complicações , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Receptores de Calcitriol/genéticaRESUMO
OBJECTIVE AND DESIGN: We performed an experimental, analytical and prospective study to evaluate the systemic activation of inflammasome in atherosclerosis' patients, in order to shed light into responsible mechanisms for plaque formation. SUBJECTS: We included sixty individuals distributed into 3 groups: 2 groups based on the report from the angiography (severe lesions - SL and primary lesions - PL) and 1 group enclosing healthy individuals (HC). METHODS: The expression assays of inflammasome genes NLRP1, NLRC4, CASP-1 and IL-1ß were performed using Real Time qPCR, with specific Taqman Assays. IL-1ß serum levels were analysed by commercial kit. Were applied the Shapiro-Wilk and Student's T-test as statistical tests. Statistical significance was set to p ≤ 0.05. RESULTS: Upregulation of NLRP1 (+3.47 FC, p = 0.0001), NLRC4 (+7.06 FC, p = 6.792 × 10-09) and IL-1ß (+2.43 FC, p = 0.005) was observed in all atherosclerosis patients when compared to HC. According to stenosis severity, patients with primary lesions showed upregulation of inflammasome genes NLRP1 (+2.87 FC, p = 0.0008), NLRC4 (+6.34 FC, p = 4.134 × 10-07) and IL-1ß (+3.39 FC, p = 0.0012) with respect to the HC group. No statistical difference was found in IL-1ß serum levels according the assessed groups. CONCLUSIONS: Inflammasome activation in atherosclerosis's patients can be systemic altered and may be triggered by NLRP1 and NLRC4 receptors. IL-1ß gene expression was identified in our study as an important systemic detectable marker of plaque severity.