DUSP12 protects against hepatic ischemia–reperfusion injury dependent on ASK1-JNK/p38 pathway in vitro and in vivo

Abstract

Hepatic ischemia-reperfusion (I/R) injury is an important risk factor resulting in liver failure during liver surgery. However, there is still lack of effective therapeutic methods to treat hepatic I/R injury. DUSP12 is a member of the dual specific phosphatase (DUSP) family. Some DUSPs have been identified as being involved in the regulation of hepatic I/R injury. However, the role of DUSP12 during hepatic I/R injury is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in a hepatic I/R injury mouse model in vivo and in hypoxia/reoxygenation (H/R) model in vitro. Using hepatocyte-specific DUSP12 knockout mice and DUSP12 transgenic mice, we demonstrated that DUSP12 apparently relieved I/R-induced liver injury. Moreover, DUSP12 inhibited hepatic inflammatory responses and alleviated apoptosis both in vitro and in vivo. Furthermore, we demonstrated that JNK and p38 activity, but not ERK1/2, was increased in the DUSP12-deficient mice and decreased in the DUSP12 transgenic mice under I/R condition. ASK1 was required for DUSP12 function in hepatic I/R injury and inhibition of ASK1 prevented inflammation and apoptosis in DUSP12-deficient hepatocytes and mice. In conclusion, DUSP12 protects against hepatic I/R injury and related inflammation and apoptosis. This regulatory role of DUSP12 is primarily through ASK1-JNK/p38 signaling pathway. Taken together, DUSP12 could be a potential therapeutic target for hepatic I/R injury.

DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs/NF-κB signaling pathway

“…Knockdown of DUSP1 reduced activation of MAPKs and NF-κB and BCG-induced release of TNF-α and IL-1β. Recent studies have confirmed that knockdown of DUSP9 36 , DUSP12 37 , DUSP14 38 and DUSP26 39 exacerbated the inflammatory response in the liver. However, in a mouse model of obesity caused by a high-fat diet, DUSP6 exhibited the opposite effect 40,41 .…”

DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs/NF-κB signaling pathway

“…Knockdown of DUSP1 reduced activation of MAPKs and NF-κB and BCG-induced release of TNF-α and IL-1β. Recent studies have con rmed that knockdown of DUSP9 33 , DUSP12 34 , DUSP14 35 and DUSP26 36 exacerbated the in ammatory response in the liver. However, in a mouse model of obesity caused by a high-fat diet, DUSP6 exhibited the opposite effect 37,38 .…”

Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

“…This can lead to inflammation and oxidative stress. The ASK1-dependent JNK/p38 signaling pathway is associated with various human diseases, such as cardiovascular diseases, diabetes, and liver diseases [ 56 – 58 ]. Studies have shown that ceramide activates ASK1 through the upregulation of TXNIP expression [ 59 ].…”