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Vitamin D₃ and monomethyl fumarate enhance natural killer cell lysis of dendritic cells and ameliorate the clinical score in mice suffering from experimental autoimmune encephalomyelitis.

Al-Jaderi Z, Maghazachi AA - Toxins (Basel) (2015)

Bottom Line: The effect of treating these mice with 1α,25-Dihydroxyvitamin D₃ (vitamin D₃), or with monomethyl fumarate (MMF) was then examined.These findings were corroborated with isolating natural killer (NK) cells from vitamin D₃-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells.The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS) is to enhance NK cell lysis of dendritic cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, POB 1103, Oslo N-0317, Norway. al-jaderi@medisin.uio.no.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) is a CD4⁺ T cell mediated inflammatory demyelinating disease that is induced in mice by administration of peptides derived from myelin proteins. We developed EAE in SJL mice by administration of PLP139-151 peptide. The effect of treating these mice with 1α,25-Dihydroxyvitamin D₃ (vitamin D₃), or with monomethyl fumarate (MMF) was then examined. We observed that both vitamin D₃ and MMF inhibited and/or prevented EAE in these mice. These findings were corroborated with isolating natural killer (NK) cells from vitamin D₃-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells. The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS) is to enhance NK cell lysis of dendritic cells.

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Vitamin D3 ameliorates the clinical score in mice with EAE and induces NK cell lysis of DCs. EAE clinical score in mice injected IP with vehicle (red line) or mice injected IP with vitamin D3 (green line) for 51 days (A). The body weight of untreated EAE mice (red line), vitamin D3 treated mice (green line), or normal mice where no disease was induced (blue line) was also examined (B). Mean ± SEM of 3 female mice ages 4–6 weeks from each group at each time point is shown. Vitamin D3 increases NK cell lysis of DCs. NK cells isolated from normal mice, EAE untreated mice or mice injected IP with vitamin D3, were examined for their ability to lyse iDCs (C) or mDCs (D). Immature DCs were generated by isolating bone marrow cells day 7 after initiation of the disease and then incubating them in vitro with murine GM-CSF plus IL-4 for 5 days (Figure 1). The cells were then incubated for an additional 2 days with LPS to generate mature DCs. E:T ratio is 50:1. Significant values were calculated using one-way ANOVA. * P < 0.001.
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toxins-07-04730-f003: Vitamin D3 ameliorates the clinical score in mice with EAE and induces NK cell lysis of DCs. EAE clinical score in mice injected IP with vehicle (red line) or mice injected IP with vitamin D3 (green line) for 51 days (A). The body weight of untreated EAE mice (red line), vitamin D3 treated mice (green line), or normal mice where no disease was induced (blue line) was also examined (B). Mean ± SEM of 3 female mice ages 4–6 weeks from each group at each time point is shown. Vitamin D3 increases NK cell lysis of DCs. NK cells isolated from normal mice, EAE untreated mice or mice injected IP with vitamin D3, were examined for their ability to lyse iDCs (C) or mDCs (D). Immature DCs were generated by isolating bone marrow cells day 7 after initiation of the disease and then incubating them in vitro with murine GM-CSF plus IL-4 for 5 days (Figure 1). The cells were then incubated for an additional 2 days with LPS to generate mature DCs. E:T ratio is 50:1. Significant values were calculated using one-way ANOVA. * P < 0.001.

Mentions: In this series of experiments, we sought to confirm the effect of injecting vitamin D3 on the development of EAE in SJL mice and correlated this effect with the ability of the drug to activate NK cells. As shown in Figure 3A, the disease developed in these mice after six days of initiation. In control mice, the trend of EAE clinical score increase was noted until day 23 after initiation and then subsided at day 30. In contrast, there was almost a complete abrogation of EAE in mice treated with vitamin D3 between 15–17 days of drug treatment. The disease rebounded in these mice after 22 days of treatment but did not reach the level of untreated mice until day 26 (Figure 3A). Further, we compared the body weight of normal mice to those mice suffering from EAE but were untreated with any drug, or in EAE mice treated with vitamin D3. Surprisingly, mice treated with vitamin D3 lost weight after 7–10 days of treatment but then restored their weight after about 12–18 days post treatment (Figure 3B). The reason behind weight loss in these mice is not clear. Similar weight loss was observed in another EAE mice model where vitamin D3 either alone or in combination with an antigen was used to treat these mice where EAE was induced with myelin oligodendrocyte glycoprotein [30].


Vitamin D₃ and monomethyl fumarate enhance natural killer cell lysis of dendritic cells and ameliorate the clinical score in mice suffering from experimental autoimmune encephalomyelitis.

Al-Jaderi Z, Maghazachi AA - Toxins (Basel) (2015)

Vitamin D3 ameliorates the clinical score in mice with EAE and induces NK cell lysis of DCs. EAE clinical score in mice injected IP with vehicle (red line) or mice injected IP with vitamin D3 (green line) for 51 days (A). The body weight of untreated EAE mice (red line), vitamin D3 treated mice (green line), or normal mice where no disease was induced (blue line) was also examined (B). Mean ± SEM of 3 female mice ages 4–6 weeks from each group at each time point is shown. Vitamin D3 increases NK cell lysis of DCs. NK cells isolated from normal mice, EAE untreated mice or mice injected IP with vitamin D3, were examined for their ability to lyse iDCs (C) or mDCs (D). Immature DCs were generated by isolating bone marrow cells day 7 after initiation of the disease and then incubating them in vitro with murine GM-CSF plus IL-4 for 5 days (Figure 1). The cells were then incubated for an additional 2 days with LPS to generate mature DCs. E:T ratio is 50:1. Significant values were calculated using one-way ANOVA. * P < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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toxins-07-04730-f003: Vitamin D3 ameliorates the clinical score in mice with EAE and induces NK cell lysis of DCs. EAE clinical score in mice injected IP with vehicle (red line) or mice injected IP with vitamin D3 (green line) for 51 days (A). The body weight of untreated EAE mice (red line), vitamin D3 treated mice (green line), or normal mice where no disease was induced (blue line) was also examined (B). Mean ± SEM of 3 female mice ages 4–6 weeks from each group at each time point is shown. Vitamin D3 increases NK cell lysis of DCs. NK cells isolated from normal mice, EAE untreated mice or mice injected IP with vitamin D3, were examined for their ability to lyse iDCs (C) or mDCs (D). Immature DCs were generated by isolating bone marrow cells day 7 after initiation of the disease and then incubating them in vitro with murine GM-CSF plus IL-4 for 5 days (Figure 1). The cells were then incubated for an additional 2 days with LPS to generate mature DCs. E:T ratio is 50:1. Significant values were calculated using one-way ANOVA. * P < 0.001.
Mentions: In this series of experiments, we sought to confirm the effect of injecting vitamin D3 on the development of EAE in SJL mice and correlated this effect with the ability of the drug to activate NK cells. As shown in Figure 3A, the disease developed in these mice after six days of initiation. In control mice, the trend of EAE clinical score increase was noted until day 23 after initiation and then subsided at day 30. In contrast, there was almost a complete abrogation of EAE in mice treated with vitamin D3 between 15–17 days of drug treatment. The disease rebounded in these mice after 22 days of treatment but did not reach the level of untreated mice until day 26 (Figure 3A). Further, we compared the body weight of normal mice to those mice suffering from EAE but were untreated with any drug, or in EAE mice treated with vitamin D3. Surprisingly, mice treated with vitamin D3 lost weight after 7–10 days of treatment but then restored their weight after about 12–18 days post treatment (Figure 3B). The reason behind weight loss in these mice is not clear. Similar weight loss was observed in another EAE mice model where vitamin D3 either alone or in combination with an antigen was used to treat these mice where EAE was induced with myelin oligodendrocyte glycoprotein [30].

Bottom Line: The effect of treating these mice with 1α,25-Dihydroxyvitamin D₃ (vitamin D₃), or with monomethyl fumarate (MMF) was then examined.These findings were corroborated with isolating natural killer (NK) cells from vitamin D₃-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells.The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS) is to enhance NK cell lysis of dendritic cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, POB 1103, Oslo N-0317, Norway. al-jaderi@medisin.uio.no.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) is a CD4⁺ T cell mediated inflammatory demyelinating disease that is induced in mice by administration of peptides derived from myelin proteins. We developed EAE in SJL mice by administration of PLP139-151 peptide. The effect of treating these mice with 1α,25-Dihydroxyvitamin D₃ (vitamin D₃), or with monomethyl fumarate (MMF) was then examined. We observed that both vitamin D₃ and MMF inhibited and/or prevented EAE in these mice. These findings were corroborated with isolating natural killer (NK) cells from vitamin D₃-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells. The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS) is to enhance NK cell lysis of dendritic cells.

Show MeSH
Related in: MedlinePlus