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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

Effect of MitoQ on human THP-1 cells. (A) IL-1 beta and (B) IL-18 release in response to H2O2 or ATP were analyzed by ELISA. Results are expressed as mean ±SE. n=5,*P<0.001. (C) The interaction between TXNIP and NLRP3 was examined by co-IP and western blotting analysis. (D) mtROS production in THP-1 cells. Cells were differentiated for 24 hours with 100 nM phorbol 12-myristate 13-acetate. Results are expressed as mean ±SE. *P<0.001.
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Figure 6: Effect of MitoQ on human THP-1 cells. (A) IL-1 beta and (B) IL-18 release in response to H2O2 or ATP were analyzed by ELISA. Results are expressed as mean ±SE. n=5,*P<0.001. (C) The interaction between TXNIP and NLRP3 was examined by co-IP and western blotting analysis. (D) mtROS production in THP-1 cells. Cells were differentiated for 24 hours with 100 nM phorbol 12-myristate 13-acetate. Results are expressed as mean ±SE. *P<0.001.

Mentions: Finally, we investigated the in vitro effect of MitoQ on IL-1 beta and IL-18 production in a human macrophage-like cell line, THP-1. ELISA analysis revealed that MitoQ dose-dependently reduces the release of these cytokines whereas it is induced by H2O2 and ATP (Figure 6A,B). Furthermore, co-IP studies revealed that TXNIP is dissociated from TRX and binds to NLRP3, and this interaction is blocked by MitoQ treatment (Figure 6C). Lastly, MitoQ also suppressed mtROS generation in a dose-dependent manner (Figure 6D). These results further confirmed the potential of MitoQ for the treatment of acute colonic injury by reducing oxidative stress and inflammatory cytokines.


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)

Effect of MitoQ on human THP-1 cells. (A) IL-1 beta and (B) IL-18 release in response to H2O2 or ATP were analyzed by ELISA. Results are expressed as mean ±SE. n=5,*P<0.001. (C) The interaction between TXNIP and NLRP3 was examined by co-IP and western blotting analysis. (D) mtROS production in THP-1 cells. Cells were differentiated for 24 hours with 100 nM phorbol 12-myristate 13-acetate. Results are expressed as mean ±SE. *P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Effect of MitoQ on human THP-1 cells. (A) IL-1 beta and (B) IL-18 release in response to H2O2 or ATP were analyzed by ELISA. Results are expressed as mean ±SE. n=5,*P<0.001. (C) The interaction between TXNIP and NLRP3 was examined by co-IP and western blotting analysis. (D) mtROS production in THP-1 cells. Cells were differentiated for 24 hours with 100 nM phorbol 12-myristate 13-acetate. Results are expressed as mean ±SE. *P<0.001.
Mentions: Finally, we investigated the in vitro effect of MitoQ on IL-1 beta and IL-18 production in a human macrophage-like cell line, THP-1. ELISA analysis revealed that MitoQ dose-dependently reduces the release of these cytokines whereas it is induced by H2O2 and ATP (Figure 6A,B). Furthermore, co-IP studies revealed that TXNIP is dissociated from TRX and binds to NLRP3, and this interaction is blocked by MitoQ treatment (Figure 6C). Lastly, MitoQ also suppressed mtROS generation in a dose-dependent manner (Figure 6D). These results further confirmed the potential of MitoQ for the treatment of acute colonic injury by reducing oxidative stress and inflammatory cytokines.

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