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Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice.

Zheng LS, Kaneko N, Sawamoto K - Front Cell Neurosci (2015)

Bottom Line: In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors.In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation.Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan ; Institute of Anatomy and Cell Biology, School of Medicine, Zhejiang University Hangzhou, China.

ABSTRACT
Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term IFN-α treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-α-induced depression are not currently understood. Neural stem cells (NSCs) in the hippocampus continuously generate new neurons, and some evidence suggests that decreased neurogenesis plays a role in the neuropathology of depression. We previously reported that IFN-α treatment suppressed hippocampal neurogenesis and induced depression-like behaviors via its receptors in the brain in adult mice. However, it is unclear how systemic IFN-α administration induces IFN-α signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors. In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-α for 5 weeks increased the production of proinflammatory cytokines, including IFN-α, and reduced neurogenesis in the hippocampus. Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation. Furthermore, minocycline treatment significantly suppressed IFN-α-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-α-induced depression, and that minocycline is a promising drug for the treatment of IFN-α-induced depression in patients, especially those who are low responders to conventional antidepressant treatments.

No MeSH data available.


Related in: MedlinePlus

IFN-α-stimulated microglia suppress proliferation of hippocampal NSCs by production and release of IFN-α. (A) Experimental design. (B) Proinflammatory cytokine levels in the conditioned media (CM) of microglia following incubation with IFN-α. The CM samples were collected before (control) or 6, 12, 18, 24, and 48 h after the 6 h incubation with IFN-α. The concentrations of IFN-α, IL-1β, IL-6, and TNF-α were quantified by ELISA and are expressed as relative values compared to the control. n = 6 cultures per group; Cnt, control. (C,D) Proliferation of the cultured hippocampal NSCs incubated with the CM from PBS or IFN-α-stimulated microglia (PBS-CM or IFN-CM, respectively), or with IFN-CM supplemented with an IFN-α neutralizing antibody (IFN-CM + IFN-α ab). NSCs were immunostained for Nestin and BrdU (C), then the percentage of BrdU+ cells in the Nestin+ population was quantified (D). n = 6 cultures per group. *P < 0.05, **P < 0.01. Error bars: means ± SEM, Scale bar, 20 μm.
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Figure 2: IFN-α-stimulated microglia suppress proliferation of hippocampal NSCs by production and release of IFN-α. (A) Experimental design. (B) Proinflammatory cytokine levels in the conditioned media (CM) of microglia following incubation with IFN-α. The CM samples were collected before (control) or 6, 12, 18, 24, and 48 h after the 6 h incubation with IFN-α. The concentrations of IFN-α, IL-1β, IL-6, and TNF-α were quantified by ELISA and are expressed as relative values compared to the control. n = 6 cultures per group; Cnt, control. (C,D) Proliferation of the cultured hippocampal NSCs incubated with the CM from PBS or IFN-α-stimulated microglia (PBS-CM or IFN-CM, respectively), or with IFN-CM supplemented with an IFN-α neutralizing antibody (IFN-CM + IFN-α ab). NSCs were immunostained for Nestin and BrdU (C), then the percentage of BrdU+ cells in the Nestin+ population was quantified (D). n = 6 cultures per group. *P < 0.05, **P < 0.01. Error bars: means ± SEM, Scale bar, 20 μm.

Mentions: To investigate the direct effects of IFN-α on microglia in vitro, microglia-derived BV-2 cells were treated with IFN-α (1 × 103 IU/ml) for 6 h. After being carefully washed to remove IFN-α, the cells were cultured in fresh medium without FBS (Figure 2A). To determine the levels of IFN-α, IL-1β, IL-6, and TNF-α released from the microglia, culture supernatants were collected at 6, 12, 18, 24, and 48 h after IFN-α removal, and analyzed by ELISA (Figure 2B). The concentrations of these cytokines were significantly increased at all time points in the IFN-α-treated group, compared with those in the PBS-treated control group, indicating that IFN-α stimulates the microglial production of proinflammatory cytokines.


Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice.

Zheng LS, Kaneko N, Sawamoto K - Front Cell Neurosci (2015)

IFN-α-stimulated microglia suppress proliferation of hippocampal NSCs by production and release of IFN-α. (A) Experimental design. (B) Proinflammatory cytokine levels in the conditioned media (CM) of microglia following incubation with IFN-α. The CM samples were collected before (control) or 6, 12, 18, 24, and 48 h after the 6 h incubation with IFN-α. The concentrations of IFN-α, IL-1β, IL-6, and TNF-α were quantified by ELISA and are expressed as relative values compared to the control. n = 6 cultures per group; Cnt, control. (C,D) Proliferation of the cultured hippocampal NSCs incubated with the CM from PBS or IFN-α-stimulated microglia (PBS-CM or IFN-CM, respectively), or with IFN-CM supplemented with an IFN-α neutralizing antibody (IFN-CM + IFN-α ab). NSCs were immunostained for Nestin and BrdU (C), then the percentage of BrdU+ cells in the Nestin+ population was quantified (D). n = 6 cultures per group. *P < 0.05, **P < 0.01. Error bars: means ± SEM, Scale bar, 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309184&req=5

Figure 2: IFN-α-stimulated microglia suppress proliferation of hippocampal NSCs by production and release of IFN-α. (A) Experimental design. (B) Proinflammatory cytokine levels in the conditioned media (CM) of microglia following incubation with IFN-α. The CM samples were collected before (control) or 6, 12, 18, 24, and 48 h after the 6 h incubation with IFN-α. The concentrations of IFN-α, IL-1β, IL-6, and TNF-α were quantified by ELISA and are expressed as relative values compared to the control. n = 6 cultures per group; Cnt, control. (C,D) Proliferation of the cultured hippocampal NSCs incubated with the CM from PBS or IFN-α-stimulated microglia (PBS-CM or IFN-CM, respectively), or with IFN-CM supplemented with an IFN-α neutralizing antibody (IFN-CM + IFN-α ab). NSCs were immunostained for Nestin and BrdU (C), then the percentage of BrdU+ cells in the Nestin+ population was quantified (D). n = 6 cultures per group. *P < 0.05, **P < 0.01. Error bars: means ± SEM, Scale bar, 20 μm.
Mentions: To investigate the direct effects of IFN-α on microglia in vitro, microglia-derived BV-2 cells were treated with IFN-α (1 × 103 IU/ml) for 6 h. After being carefully washed to remove IFN-α, the cells were cultured in fresh medium without FBS (Figure 2A). To determine the levels of IFN-α, IL-1β, IL-6, and TNF-α released from the microglia, culture supernatants were collected at 6, 12, 18, 24, and 48 h after IFN-α removal, and analyzed by ELISA (Figure 2B). The concentrations of these cytokines were significantly increased at all time points in the IFN-α-treated group, compared with those in the PBS-treated control group, indicating that IFN-α stimulates the microglial production of proinflammatory cytokines.

Bottom Line: In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors.In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation.Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan ; Institute of Anatomy and Cell Biology, School of Medicine, Zhejiang University Hangzhou, China.

ABSTRACT
Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term IFN-α treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-α-induced depression are not currently understood. Neural stem cells (NSCs) in the hippocampus continuously generate new neurons, and some evidence suggests that decreased neurogenesis plays a role in the neuropathology of depression. We previously reported that IFN-α treatment suppressed hippocampal neurogenesis and induced depression-like behaviors via its receptors in the brain in adult mice. However, it is unclear how systemic IFN-α administration induces IFN-α signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors. In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-α for 5 weeks increased the production of proinflammatory cytokines, including IFN-α, and reduced neurogenesis in the hippocampus. Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation. Furthermore, minocycline treatment significantly suppressed IFN-α-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-α-induced depression, and that minocycline is a promising drug for the treatment of IFN-α-induced depression in patients, especially those who are low responders to conventional antidepressant treatments.

No MeSH data available.


Related in: MedlinePlus