Dataset Information

Protein nitration is predominantly mediated by a peroxynitrite-dependent pathway in cultured human leucocytes.

ABSTRACT: Protein nitration is a common characteristic of oxidative injury caused by the invasion of leucocytes into inflammatory lesions. Two distinct pathways of nitration of protein tyrosine residues, namely the peroxynitrite (ONOO(-))-mediated pathway and another catalysed by the haem-containing peroxidases, have been reported under experimental conditions. However, the contribution of these two pathways in human leucocytes is still controversial. The present study demonstrates that the process of phenolic nitration of proteins in cultured human leucocytes is mainly ONOO(-)-mediated and that it differs between granulocytes and mononuclear cells, depending on the cell compartment and the stimuli. We have also shown that NO induces protein nitration via a ONOO(-)-dependent pathway, whereas NO(2)(-), the NO metabolite, does not increase but decreases nitration in PMA-stimulated leucocytes. The inhibition of myeloperoxidase activity did not reduce protein nitration; on the other hand, the myeloperoxidase inhibitor aminobenzoic hydrazide caused increased nitration, which was mediated by ONOO(-). These results suggest that protein nitration is predominantly mediated by a ONOO(-)-dependent pathway in cultured human leucocytes and that the myeloperoxidase-catalysed pathway does not play a significant role in protein nitration.

SUBMITTER: Galinanes M

PROVIDER: S-EPMC1222891 | biostudies-other | 2002 Oct

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:T-helper 17 cells and regulatory T cells (Treg) are critical regulators in the pathogenesis of multiple sclerosis (MS) but the factors affecting Treg/Th17 balance remains largely unknown. Redox balance is crucial to maintaining immune homeostasis and reducing the severity of MS but the underlying mechanisms are unclear yet. Herein, we tested the hypothesis that peroxynitrite, a representative molecule of reactive nitrogen species (RNS), could inhibit peripheral Treg cells, disrupt Treg/Th17 balance and aggravate MS pathology by inducing nitration of interleukin-2 receptor (IL-2R) and down-regulating RAS/JNK-AP-1 signalling pathway. Experimental autoimmune encephalomyelitis (EAE) mouse model and serum samples of MS patients were used in the study. We found that the increases of 3-nitrotyrosine and IL-2R nitration in Treg cells were coincided with disease severity in the active EAE mice. Mechanistically, peroxynitrite-induced IL-2R nitration down-regulated RAS/JNK signalling pathway, subsequently impairing peripheral Treg expansion and function, increasing Teff infiltration into the central nerve system (CNS), aggravating demyelination and neurological deficits in the EAE mice. Those changes were abolished by peroxynitrite decomposition catalyst (PDC) treatment. Furthermore, transplantation of the PDC-treated-autologous Treg cells from donor EAE mice significantly decreased Th17 cells in both axillary lymph nodes and lumbar spinal cord, and ameliorated the neuropathology of the recipient EAE mice. Those results suggest that peroxynitrite could disrupt peripheral Treg/Th17 balance, and aggravate neuroinflammation and neurological deficit in active EAE/MS pathogenesis. The underlying mechanisms are related to induce the nitration of IL-2R and inhibit the RAS/JNK-AP-1 signalling pathway in Treg cells. The study highlights that targeting peroxynitrite-mediated peripheral IL-2R nitration in Treg cells could be a novel therapeutic strategy to restore Treg/Th17 balance and ameliorate MS/EAE pathogenesis. The study provides valuable insights into potential role of peripheral redox balance in maintaining CNS immune homeostasis.

Dataset Information

Protein nitration is predominantly mediated by a peroxynitrite-dependent pathway in cultured human leucocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets