Arginine transport and nitric oxide production: role in the inflammatory response

Abstract

The research concerns the characterization of the pathways responsible for the recruitment of L-arginine, the obliged substrate for nitric oxide biosynthesis, in human cells. Endothelial cells and monocytes/macrophages have been employed, as the cell types more directly linked to NO pathway. As for human endothelium, only system y+ is involved in the inflammatory response: both TNFα and rapamycin, an mTOR inhibitor employed in clinical angioplasty, lead to a massive increase of CAT-mediated arginine influx and to the activation of endothelial cells; however, both compounds are ineffective in stimulating the synthesis of NO, and even diminish the expression of eNOS mRNA and protein. Rapamycin also causes a significant loss of cell viability and function, thus confirming the adverse effects of the drug observed in vivo. Among cells of the human monocyte/macrophage lineage, differences in the modulation of arginine transport by cytokines have emerged: IFNγ stimulates system y+L activity in blood monocytes, while alveolar macrophages are insensitive to inflammatory stimuli; also in these models, the production of NO is undetectable even in the presence of inflammatory cytokines. The supposed co-induction of arginine transport and NO biosynthesis under inflammatory conditions may thus not be valid for human cells, although plausible in animal models.