IL-10 Gene Knockout Reduces the Expression of mGlu Receptor 1a/b and Decreases the Glutamate-Dependent Production of Nitric Oxide

Abstract

IL-10 provides trophic and survival effects directly on neurons, promotes axonal outgrowth, and stimulates neuroregeneration. In this study, we analyzed the activities of arginase and nitric oxide synthase (NOS) in synaptoneurosomes derived from brain cortex of C57BL/6 IL-10 gene-knockout (KO) and wild-type (Wt) mice and determined that the synaptoneurosomes derived from KO mice present lower arginase II activity and lower spermine content than those derived from Wt mice, whereas the basal NOS activity in the KO synaptoneurosomes was higher than that observed in the control synaptoneurosomes. Moreover, our results indicate that the plasma membranes isolated from the KO mice brain exhibit significantly lower spermine-induced enhancement of [ 3 H] MK-801 binding than the plasma membranes from the brain of Wt mice. Glutamate increases the production of nitric oxide (NO) in Wt synaptoneurosomes in a dose-dependent manner, whereas in the KO synaptoneurosomes, this amino acid does not affect the synthesis of NO. The glutamate-dependent acceleration of NO synthesis in Wt synaptoneurosomes was abrogated by LY367385, an antagonist of mGluR1a/b. The western blot analysis of the synaptoneurosomal proteins demonstrates that the expression of the subunits of NMDAR (NMDAR2A and NMDAR2B), the level of NMDAR-bound nNOS and the expression of iNOS are not changed in KO mice and that only the level of mGluR1a/b is markedly reduced in the synaptoneurosomes of KO mice. We conclude that a neuroprotective and neuroregenerative property of IL-10, in addition to its effects on polyamine metabolism and the spermine-dependent modulation of NMDAR, may involve the regulation of mGluR1a/b expression.

Knockdown of interleukin-10 induces the redistribution of sigma1-receptor and increases the glutamate-dependent NADPH-oxidase activity in mouse brain neurons

“…Our previous investigation has shown that the total level of the subunits of NMDAR (NR2A and NR2B), as well as the level of NMDAR-bound nNOS, are not changed in KO mice. Despite this, NMDAR from KO mice has different ligand-binding properties and exhibits significantly lower sensitivity to polyamines [ 10 ]. These data suggests that IL-10 deficient mice are comprising splicing isoforms of NMDAR, which may have higher sensitivity to the protective actions of SigR1.…”

“…IL-10 can change long-term potentiation, suggesting that a target of the cytokine is the system participating in glutamatergic neurotransmission [ 9 ]. An IL-10 deficiency reduces the expression of mGlu-receptor 1a/b, decreases the sensitivity of NMDA-receptor to the polyamines and changes the glutamate-dependent production of nitric oxide [ 10 ]. In addition to an activation of the canonical signaling pathways, this cytokine is capable of exerting the rapid neuroprotective effects through inhibition of inositol-3-phosphate receptor (IP3R)-sensitive Ca 2+ release from internal stores after repeated NMDA receptor stimulation [ 11 ].…”