A growing number of diseases in humans, including trauma, certain cancers, and infection, are known to be associated with l-arginine deficiency. In addition, l-arginine must be supplemented by diet during pregnancy to aid fetal development. In conditions of l-arginine depletion, T cell proliferation is impaired. We have previously shown that neonatal blood has lower l-arginine levels than adult blood, which is associated with poor neonatal lymphocyte proliferation, and that l-arginine enhances neonatal lymphocyte proliferation through an interleukin (IL)-2-independent pathway. In this study, we have further investigated how exogenous l-arginine enhances neonatal regulatory T-cells (Tregs) function in relation to IL-10 production under epigenetic regulation. Results showed that cord blood mononuclear cells (CBMCs) produced higher levels of IL-10 than adult peripheral blood mononuclear cells (PBMCs) by phytohemagglutinin stimulation but not by anti-CD3/anti-CD28 stimulation. Addition of exogenous l-arginine had no effect on transforming growth factor-β production by PBMCs or CBMCs, but enhanced IL-10 production by neonatal CD4+CD25+FoxP3+ Tregs. Further studies showed that IL-10 promoter DNA hypomethylation, rather than histone modification, corresponded to the l-arginine-induced increase in IL-10 production by neonatal CD4+ T cells. These results suggest that l-arginine modulates neonatal Tregs through the regulation of IL-10 promoter DNA methylation. l-arginine supplementation may correct the Treg function in newborns with l-arginine deficiency.
Human urine contains several macromolecules which inhibit calcium oxalate crystallization. Osteopontin (or uropontin), a secreted phosphoglycoprotein with the amino acid sequence Arg-Gly-Asp (RGD) and high affinity to hydroxyapatite, is one such inhibitor. To investigate the action of this protein on renal stone formation, the expression osteopontin gene in normal and chemically induced urolithiasis rat kidney was compared at both mRNA and protein levels. Northern blot analysis shown a significant increase of osteopontin mRNA level in stone-forming rat kidney compared with normal ones. In an in situ hybridization study, we localized the transcripts of the osteopontin gene in epithelial cells of both distal and collective tubules, and found a remarkably strong signal in stone-forming rats. The amount and distribution of the protein in kidney from immunocytochemistry staining showed the same pattern as seen in situ hybridization. These findings indicate that osteopontin may be an important macromolecule in the normal endogenous defence against the formation of urinary calculi.
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