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001-es BibID:BIBFORM055320
Első szerző:Szabó Attila (molekuláris biológus, immunológus, filozófus)
Cím:Activation of the sigma-1 receptor by specific ligands inhibits human inflammatory dendritic cell functions and effector t-lymphocyte responses / Attila Szabo, Attila Kovacs, Ede Frecska, Eva Rajnavolgyi
Dátum:2014
ISSN:1552-5260
Megjegyzések:Background: Neuropsychiatric diseases have recently been attributed to chronic inflammation in the central nervous system, and correlation between gene polymorphisms of innate immune receptors and the frequency of late onset of Alzheimer's disease (AD) has also been shown. Ligation of murine maternal Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) by LPS or PolyI:C have been shown to cause decreased neurogenesis, cognitive deficits, and increased deposition of A? aggregates in the brain of the offsprings. These data in line with the accumulation of monocyte-derived dendritic cells (moDCs) and macrophages during chronic inflammation suggest an activation-induced disease promoting mechanism. In contrast, the orphan receptor sigma-1 has been shown to mediate anti-inflammatory responses in rodent in vivo models, but the molecular background has not been elucidated.Methods: Western blot was used to monitor protein level expression of SIGMAR1 in human primary monocytes, macrophages and moDCs. Gene expression of sigma-1 receptor (SIGMAR1), and IL-1b, IL-6, TNFa, IL-8, IL-10 cytokines was assessed by Q-PCR. Concentration of secreted cytokines was measured by ELISA. ELISPOT was used to assess the numbers of moDC-primed autologous naïve Th1 and Th17 cells. Gene-specific RNA-interference was performed to silence sigmar-1 gene. N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and PRE-084 hydrochloride were used to trigger SIGMAR1 in moDCs. To mimic different inflammatory conditions, we used TLR/RLR ligands (LPS, PolyI:C) and inactivated pathogens (E. coli and influenza virus).Results: In this study we used endogenous ligands (NN-DMT, 5-MeO-DMT) and high affinity synthetic PRE-084-hydrochloride to trigger sigma-1 in human moDCs and monitored their effects on LPS- and polyI:C-induced inflammatory responses. Co-administration of sigma-1 ligands with these activators inhibited the production of pro-inflammatory cytokines and chemokines (IL-1b, IL-6, TNFa, IL-8), while increased the secretion of anti-inflammatory IL-10. The antigen-presenting capacity of moDCs was also inhibited and co-administration of sigma-1 ligands with E. coli or influenza virus decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector cells in a sigma-1 receptor specific manner confirmed by gene silencing.Conclusions: These results demonstrate the inhibitory potential of stimulated sigma-1 receptor in brain-resident moDCs that could be harnessed for the pharmacological treatment of AD and other chronic inflammatory conditions in the CNS.
Tárgyszavak:Orvostudományok Elméleti orvostudományok poszter
inflammation
dendritic cells
psychedelics
dimethyltryptamine
anti-inflammatory agents
sigma-1 receptor
neuroinflammation
Megjelenés:Alzheimer's & Dementia. - 10 : 4 (2014), p. P876. -
További szerzők:Kovács Attila Frecska Ede (1953-) (pszichiáter) Rajnavölgyi Éva (1950-) (immunológus)
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2.

001-es BibID:BIBFORM054457
035-os BibID:Article ID: e106533
Első szerző:Szabó Attila (molekuláris biológus, immunológus, filozófus)
Cím:Psychedelic N,N-Dimethyltryptamine and 5-Methoxy- N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells / Attila Szabo, Attila Kovacs, Ede Frecska, Eva Rajnavolgyi
Dátum:2014
ISSN:1932-6203
Megjegyzések:The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1?, IL-6, TNF? and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
psychedelics
N,N-dimethyltryptamine
5-methoxy-N,N-dimethyltryptamine
sigma-1 receptor
innate immunity
inflammation
dendritic cell
Megjelenés:Plos One. - 9 : 8 (2014), [12] p. -
További szerzők:Kovács Attila Frecska Ede (1953-) (pszichiáter) Rajnavölgyi Éva (1950-) (immunológus)
Pályázati támogatás:4.2.4. A/2-11-1-2012-0001
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DOI
Intézményi repozitóriumban (DEA) tárolt változat
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