Interleukin-37 (IL-37), a member of the IL-1 family, primarily functions as an anti-inflammatory cytokine, reducing inflammation and suppressing the immune response. However, the expression and role of IL-37 in tuberculosis (TB) remains unknown. We aimed to measure serum levels of IL-37 and several important cytokines in 25 patients with active TB and to analyse their association with disease activity. We found that IL-37 levels decreased in patients with TB and recovered after treatment. IL-37 levels negatively correlated with the serum concentration of IFN-c and IL-12 but positively correlated with IL-10 and TGFb levels. After IL-37, secretion was blocked in peripheral blood mononuclear cells from active patients with TB, IFN-c and IL-10 production was significantly upregulated; this was not observed in healthy donors or patients after treatment. IL-37 knockdown significantly enhanced the phagocytic activity of THP1-derived macrophages towards Mycobacterium tuberculosis (M. tb). M1/M2 polarization-associated markers were detected simultaneously, and IL-37 induced a phenotypic shift in THP1-derived macrophages towards a high CD206 + and low CD86 + macrophage subtype. Furthermore, this phenotypic shift was accompanied by upregulated mRNA levels of arginase 1, TGF-b and IL-10, which are characteristic hallmarks of M2 macrophages. In conclusion, our results suggest that increased levels of IL-37 in patients with TB are associated with IFN-c, IL-12, IL-10 and TGF-b levels and that IL-37 plays a pathological role in TB infection by inhibiting the production of pro-inflammatory cytokines and inducing macrophages towards an M2-like phenotype. Thus, IL-37 may be a novel research target to understand the pathogenesis of TB infection.
The underlying mechanisms that mediate the effects of vitamin C on endothelial cell aging are widely unknown. To investigate whether Piwi-interacting RNAs (piRNAs) are involved in this process, an endothelial aging model was induced in vitro using H2O2 in human umbilical vein endothelial cells (HUVECs) and then treated with vitamin C (VC). Untreated HUVECs without H2O2 exposure were used to serve as the negative control group. Cell cycle, cell viability, and aging-associated protein expression were assessed, and RNA sequencing was performed to reveal the piRNA profile. Functional and regulatory networks of the different piRNA target genes were predicted by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. H2O2 induced G1 phase cell arrest, decreased cell viability, and upregulated the senescence marker p16 in HUVECs. We found that VC treatment inhibited G1 phase cell arrest, increased the number of cells in the S and G2/M phases, increased cell viability, and decreased p16 expression. The piRNA expression profiles revealed that a large proportion of piRNAs that were differentially expressed in H2O2-treated HUVECs were partly normalized by VC. Furthermore, a number of piRNAs associated with the response to VC in H2O2-treated HUVECs were linked with senescence and cell cycle-related pathways and networks. These results indicate that the ability of VC to attenuate H2O2-mediated endothelial cell senescence may be associated with changes in expression of piRNAs that are linked to the cell cycle.
Vitamin C plays a protective role in oxidative damage by blocking the effects of free radicals. The present study investigated the mechanisms through which vitamin C partly mediates anti-apoptotic and antioxidant functions via the regulation of microRNAs (miRNAs or miRs). For this purpose, a global miRNA expression analysis on human umbilical vein endothelial cells (HUVECs) treated with vitamin C was conducted using microarrays containing human precursor and mature miRNA probes. The results revealed that there were 42 identical miRNAs among the differentially expressed miRNAs in the HUVEC group and H 2 O 2 + vitamin C-treated HUVEC group compared to the H 2 O 2 -exposed HUVEC group, including 41 upregulated miRNAs and 1 down-regulated miRNA. Using bioinformatics analysis, differentially expressed miRNAs were investigated to identify novel target mRNAs and signaling pathways. Pathway enrichment analyses revealed that apoptosis, the mitogen-activated protein kinase (MAPK) signaling pathway, phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and oxidative phosphorylation were significantly enriched. The results from western blot analysis demonstrated that the interleukin (IL)10, matrix metalloproteinase (MMP)2, cAMP-response element binding protein (CREB) and p-CREB protein expression levels in HUVECs transfected with hsa-miR-3928-5p and induced by H 2 O 2 were significantly downregulated; the MAPK9, caspase-3 (CASP3) and p-CASP3 protein expression levels in HUVECs transfected with hsa-miR-323a-5p and induced by H 2 O 2 were significantly downregulated. The present study therefore demonstrates that vitamin C partly exerts protective effects on HUVECs through the regulation of miRNA/mRNA axis expression.
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