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Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells.

Onodera Y, Teramura T, Takehara T, Shigi K, Fukuda K - FEBS Open Bio (2015)

Bottom Line: Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression.Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo.From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine, Osaka, Japan.

ABSTRACT
Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases.

No MeSH data available.


Related in: MedlinePlus

TAK1 is involved in H2O2 mediated activation of MAPKs and NF-κB signaling cascades. (A) WB analysis for the phosphorylated status of MAPKs and IκB in the cells treated with H2O2 and TAK1 inhibitor. (B) pPCR analysis for Cox-2 expression in the cells treated with H2O2 and TAK1 inhibitor. (C) WB analysis for Cox-2 expression after H2O2 stimulation and TAK1 inhibition. (D) ELISA analysis for PGE2 expression after H2O2 stimulation and TAK1 inhibition.
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f0015: TAK1 is involved in H2O2 mediated activation of MAPKs and NF-κB signaling cascades. (A) WB analysis for the phosphorylated status of MAPKs and IκB in the cells treated with H2O2 and TAK1 inhibitor. (B) pPCR analysis for Cox-2 expression in the cells treated with H2O2 and TAK1 inhibitor. (C) WB analysis for Cox-2 expression after H2O2 stimulation and TAK1 inhibition. (D) ELISA analysis for PGE2 expression after H2O2 stimulation and TAK1 inhibition.

Mentions: Since multiple MAPKs and NF-κB were simultaneously activated by ROS, we hypothesized that some upstream molecules were responsible for the ROS-induced up-regulation of Cox-2 and PGE2 expressions. Accumulating evidence suggests the involvement of TAK1 in the ROS-induced MAPKs activation [28,29]. Thus we looked at the effect of H2O2 in the phosphorylation of TAK1 and found that H2O2 clearly caused the phosphorylation of TAK1 in the SFs. Supplementation of TAK1 inhibitor blocked phosphorylation of the downstream molecules p38, Erk and NF-κB, respectively (Fig. 3A). Importantly, Inhibition of TAK1 during H2O2 treatment blocked both the expression of Cox-2 and PGE2 completely on RNA (Fig. 3B) and protein levels (Fig. 3C and D). This action was conserved in other cell types (Supplement 1).


Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells.

Onodera Y, Teramura T, Takehara T, Shigi K, Fukuda K - FEBS Open Bio (2015)

TAK1 is involved in H2O2 mediated activation of MAPKs and NF-κB signaling cascades. (A) WB analysis for the phosphorylated status of MAPKs and IκB in the cells treated with H2O2 and TAK1 inhibitor. (B) pPCR analysis for Cox-2 expression in the cells treated with H2O2 and TAK1 inhibitor. (C) WB analysis for Cox-2 expression after H2O2 stimulation and TAK1 inhibition. (D) ELISA analysis for PGE2 expression after H2O2 stimulation and TAK1 inhibition.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476901&req=5

f0015: TAK1 is involved in H2O2 mediated activation of MAPKs and NF-κB signaling cascades. (A) WB analysis for the phosphorylated status of MAPKs and IκB in the cells treated with H2O2 and TAK1 inhibitor. (B) pPCR analysis for Cox-2 expression in the cells treated with H2O2 and TAK1 inhibitor. (C) WB analysis for Cox-2 expression after H2O2 stimulation and TAK1 inhibition. (D) ELISA analysis for PGE2 expression after H2O2 stimulation and TAK1 inhibition.
Mentions: Since multiple MAPKs and NF-κB were simultaneously activated by ROS, we hypothesized that some upstream molecules were responsible for the ROS-induced up-regulation of Cox-2 and PGE2 expressions. Accumulating evidence suggests the involvement of TAK1 in the ROS-induced MAPKs activation [28,29]. Thus we looked at the effect of H2O2 in the phosphorylation of TAK1 and found that H2O2 clearly caused the phosphorylation of TAK1 in the SFs. Supplementation of TAK1 inhibitor blocked phosphorylation of the downstream molecules p38, Erk and NF-κB, respectively (Fig. 3A). Importantly, Inhibition of TAK1 during H2O2 treatment blocked both the expression of Cox-2 and PGE2 completely on RNA (Fig. 3B) and protein levels (Fig. 3C and D). This action was conserved in other cell types (Supplement 1).

Bottom Line: Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression.Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo.From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine, Osaka, Japan.

ABSTRACT
Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases.

No MeSH data available.


Related in: MedlinePlus