TY  - GEN
AU  - Gazdić, Marina
AU  - Simović Marković, Bojana
AU  - Vučićević, Ljubica
AU  - Nikolić, Tamara
AU  - Đonov, Valentin
AU  - Arsenijević, Nebojša
AU  - Trajković, Vladimir
AU  - Lukić, Miodrag L.
AU  - Volarević, Vladislav
PY  - 2018
UR  - http://doi.wiley.com/10.1002/term.2452
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2833
AB  - The effects of mesenchymal stem cells (MSCs) on the phenotype and function of natural killer T (NKT) cells is not understood. We used concanavalin A (Con A) and α-galactosylceramide (α-GalCer)-induced liver injury to evaluate the effects of MSCs on NKT-dependent hepatotoxicity. Mouse MSCs (mMSCs) significantly reduced Con A- and α-GalCer-mediated hepatitis in C57Bl/6 mice, as demonstrated by histopathological and biochemical analysis, attenuated the influx of inflammatory [T-bet + , tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ)-producing and GATA3 + , interleukin-4 (IL-4)-producing] liver NKT cells and downregulated TNF-α, IFN-γ and IL-4 levels in the sera. The liver NKT cells cultured in vitro with mMSCs produced lower amounts of inflammatory cytokines (TNF-α, IFN-γ, IL-4) and higher amounts of immunosuppressive IL-10 upon α-GalCer stimulation. mMSC treatment attenuated expression of apoptosis-inducing ligands on liver NKT cells and suppressed the expression of pro-apoptotic genes in the livers of α-GalCer-treated mice. mMSCs reduced the cytotoxicity of liver NKT cells against hepatocytes in vitro. The presence of 1-methyl-dl-tryptophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), or l-N G -monomethyl arginine citrate, a specific inhibitor of inducible nitric oxide synthase (iNOS), in mMSC-conditioned medium injected into α-GalCer-treated mice, counteracted the hepatoprotective effect of mMSCs in vivo and restored pro-inflammatory cytokine production and cytotoxicity of NKT cells in vitro. Human MSCs attenuated the production of inflammatory cytokines in α-GalCer-stimulated human peripheral blood mononuclear cells in an iNOS- and IDO-dependent manner and reduced their cytotoxicity against HepG2 cells. In conclusion, MSCs protect from acute liver injury by attenuating the cytotoxicity and capacity of liver NKT cells to produce inflammatory cytokines in an iNOS- and IDO-dependent manner.
T2  - Journal of Tissue Engineering and Regenerative Medicine
T1  - Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner
IS  - 2
VL  - 12
DO  - 10.1002/term.2452
SP  - e1173
EP  - e1185
ER  - 

@misc{
author = "Gazdić, Marina and Simović Marković, Bojana and Vučićević, Ljubica and Nikolić, Tamara and Đonov, Valentin and Arsenijević, Nebojša and Trajković, Vladimir and Lukić, Miodrag L. and Volarević, Vladislav",
year = "2018",
abstract = "The effects of mesenchymal stem cells (MSCs) on the phenotype and function of natural killer T (NKT) cells is not understood. We used concanavalin A (Con A) and α-galactosylceramide (α-GalCer)-induced liver injury to evaluate the effects of MSCs on NKT-dependent hepatotoxicity. Mouse MSCs (mMSCs) significantly reduced Con A- and α-GalCer-mediated hepatitis in C57Bl/6 mice, as demonstrated by histopathological and biochemical analysis, attenuated the influx of inflammatory [T-bet + , tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ)-producing and GATA3 + , interleukin-4 (IL-4)-producing] liver NKT cells and downregulated TNF-α, IFN-γ and IL-4 levels in the sera. The liver NKT cells cultured in vitro with mMSCs produced lower amounts of inflammatory cytokines (TNF-α, IFN-γ, IL-4) and higher amounts of immunosuppressive IL-10 upon α-GalCer stimulation. mMSC treatment attenuated expression of apoptosis-inducing ligands on liver NKT cells and suppressed the expression of pro-apoptotic genes in the livers of α-GalCer-treated mice. mMSCs reduced the cytotoxicity of liver NKT cells against hepatocytes in vitro. The presence of 1-methyl-dl-tryptophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), or l-N G -monomethyl arginine citrate, a specific inhibitor of inducible nitric oxide synthase (iNOS), in mMSC-conditioned medium injected into α-GalCer-treated mice, counteracted the hepatoprotective effect of mMSCs in vivo and restored pro-inflammatory cytokine production and cytotoxicity of NKT cells in vitro. Human MSCs attenuated the production of inflammatory cytokines in α-GalCer-stimulated human peripheral blood mononuclear cells in an iNOS- and IDO-dependent manner and reduced their cytotoxicity against HepG2 cells. In conclusion, MSCs protect from acute liver injury by attenuating the cytotoxicity and capacity of liver NKT cells to produce inflammatory cytokines in an iNOS- and IDO-dependent manner.",
journal = "Journal of Tissue Engineering and Regenerative Medicine",
title = "Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner",
number = "2",
volume = "12",
doi = "10.1002/term.2452",
pages = "e1173-e1185"
}

Gazdić, M., Simović Marković, B., Vučićević, L., Nikolić, T., Đonov, V., Arsenijević, N., Trajković, V., Lukić, M. L.,& Volarević, V.. (2018). Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner. in Journal of Tissue Engineering and Regenerative Medicine, 12(2), e1173-e1185.
https://doi.org/10.1002/term.2452

Gazdić M, Simović Marković B, Vučićević L, Nikolić T, Đonov V, Arsenijević N, Trajković V, Lukić ML, Volarević V. Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner. in Journal of Tissue Engineering and Regenerative Medicine. 2018;12(2):e1173-e1185.
doi:10.1002/term.2452 .

Gazdić, Marina, Simović Marković, Bojana, Vučićević, Ljubica, Nikolić, Tamara, Đonov, Valentin, Arsenijević, Nebojša, Trajković, Vladimir, Lukić, Miodrag L., Volarević, Vladislav, "Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner" in Journal of Tissue Engineering and Regenerative Medicine, 12, no. 2 (2018):e1173-e1185,
https://doi.org/10.1002/term.2452 . .