Abstract
BackgroundIn the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. This cytokine is primarily produced by glial cells and has beneficial effects on the neuronal viability. However, the mechanisms of IL-10-elicited neuroprotection are not clear.ResultsMembrane preparations, isolated from wild-type (Wt) and IL-10 knockout (KO) mice brain were used in this study. It has been shown that compared to wild-type mice, in IL-10 KO mice brain, the amount of immunoglobulin binding protein (BiP) is greatly increased, whereas the content of sigma receptor-1 (SigR1) is not changed significantly. Co-immunoprecipitation experiments have shown that the association of SigR1 with small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1), NR2B subunit of NMDA-receptor (NMDAR) and inositol-3-phosphate receptor (IP3R) is higher in the IL-10 KO mice brain than in the Wt mice brain. Besides, we have found that either glutamate or sigma ligands, separately or together, do not change glutamate-induced NADPH-oxidase (NOX) activity in Wt-type mice brain membrane preparations, whereas in IL-10 KO mice high concentration of glutamate markedly increases the NOX-dependent production of reactive oxygen species (ROS). Glutamate-dependent ROS production was decreased to the normal levels by the action of sigma-agonists.ConclusionsIt has been concluded that IL-10 deprivation, at least in part, can lead to the induction of ER-stress, which causes BiP expression and SigR1 redistribution between components of endoplasmic reticulum (ER) and plasma membrane. Moreover, IL-10 deficiency can change the specific organization of NMDAR, increasing the surface expression of SigR1-sensitive NR2B-containing NMDAR. In these conditions, glutamate-dependent ROS production is greatly increased leading to the initiation of apoptosis. In this circumstances, sigma-ligands could play a preventive role against NMDA receptor-mediated excitotoxicity.
Highlights
In the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions
To study the possible involvement of the IL-10 in the endoplasmic reticulum (ER) stress in the neurons we tested the content of two chaperone proteins—binding protein (BiP) and sigma receptor-1 (SigR1) in the IL-10 KO mice brain
We have found that the amount of BiP is greatly increased in the KO mice brain, whereas the content of SigR1 is not changed significantly (Fig. 1a, b)
Summary
In the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. Deprivation of IL-10, through modification of IP3R may initiate ER-stress and uncontrolled release of Ca2+, which is characterized by a redistribution of ER-responses chaperones and increased production of ROS [12] In these perturbations, NADPH oxidase may play the significant role, as a primary source of ROS produced in the result of NMDA-receptor overactivation [13]. In IL-10 KO mice brain the association of SigR1 with IP3R and Rac (Ras-related C3 botulinum toxin substrate 1), as well as with NR2B subunit of NMDAR is increased that leads to the glutamate-dependent and SigR1-sensitive activation of NADPH-oxidase (NOX) These data suggest that IL-10 can decrease the NMDARdependent production of ROS during the ER-stress through modulation of SigR1 that may be important for understanding the mechanisms of neuroprotective action of IL-10
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
