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Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines.

Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS - BMC Med (2013)

Bottom Line: The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.

ABSTRACT

Background: MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.

Methods: Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.

Results: Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.

Conclusion: Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

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Related in: MedlinePlus

Schematic representation of the mechanism of action of MitoQ during colitis. Increased generation of mtROS in the damaged epithelium and activated macrophages leads to dissociation of TXNIP from the TXNIP-TRX complex. Dissociated TXNIP binds to NLRP3 protein and activates the NLRP3 inflammasome complex, which is responsible for cleavage of pro-inflammatory cytokines pro-IL-1 beta and pro-IL-18 into their active forms, thereby increasing intestinal permeability and tissue injury. Moreover, the NLRP3 inflammasome complex activates the adaptive immune system and exacerbates inflammation. Suppressing mtROS with MitoQ can suppress this pathway and inhibit cytokines release, thereby ameliorating inflammation during colitis.
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Figure 7: Schematic representation of the mechanism of action of MitoQ during colitis. Increased generation of mtROS in the damaged epithelium and activated macrophages leads to dissociation of TXNIP from the TXNIP-TRX complex. Dissociated TXNIP binds to NLRP3 protein and activates the NLRP3 inflammasome complex, which is responsible for cleavage of pro-inflammatory cytokines pro-IL-1 beta and pro-IL-18 into their active forms, thereby increasing intestinal permeability and tissue injury. Moreover, the NLRP3 inflammasome complex activates the adaptive immune system and exacerbates inflammation. Suppressing mtROS with MitoQ can suppress this pathway and inhibit cytokines release, thereby ameliorating inflammation during colitis.

Mentions: Finally, we conclude that overgeneration of mtROS during IBD leads to increase of inflammatory cytokines IL-1 beta and IL-18 via activation of the NLRP3 inflammasome. Active inflammatory cytokines increase intestinal permeability, tissue injury and decreasing mtROS with MitoQ can suppress this pathway and ameliorate inflammation during colitis (FigureĀ 7).


Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines.

Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS - BMC Med (2013)

Schematic representation of the mechanism of action of MitoQ during colitis. Increased generation of mtROS in the damaged epithelium and activated macrophages leads to dissociation of TXNIP from the TXNIP-TRX complex. Dissociated TXNIP binds to NLRP3 protein and activates the NLRP3 inflammasome complex, which is responsible for cleavage of pro-inflammatory cytokines pro-IL-1 beta and pro-IL-18 into their active forms, thereby increasing intestinal permeability and tissue injury. Moreover, the NLRP3 inflammasome complex activates the adaptive immune system and exacerbates inflammation. Suppressing mtROS with MitoQ can suppress this pathway and inhibit cytokines release, thereby ameliorating inflammation during colitis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750576&req=5

Figure 7: Schematic representation of the mechanism of action of MitoQ during colitis. Increased generation of mtROS in the damaged epithelium and activated macrophages leads to dissociation of TXNIP from the TXNIP-TRX complex. Dissociated TXNIP binds to NLRP3 protein and activates the NLRP3 inflammasome complex, which is responsible for cleavage of pro-inflammatory cytokines pro-IL-1 beta and pro-IL-18 into their active forms, thereby increasing intestinal permeability and tissue injury. Moreover, the NLRP3 inflammasome complex activates the adaptive immune system and exacerbates inflammation. Suppressing mtROS with MitoQ can suppress this pathway and inhibit cytokines release, thereby ameliorating inflammation during colitis.
Mentions: Finally, we conclude that overgeneration of mtROS during IBD leads to increase of inflammatory cytokines IL-1 beta and IL-18 via activation of the NLRP3 inflammasome. Active inflammatory cytokines increase intestinal permeability, tissue injury and decreasing mtROS with MitoQ can suppress this pathway and ameliorate inflammation during colitis (FigureĀ 7).

Bottom Line: The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.

ABSTRACT

Background: MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.

Methods: Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.

Results: Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.

Conclusion: Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus