Study On The Role Of MAPK Phosphatase Regulating Nrf2 Signaling Pathway

The nuclear factor erythroid-2 related factor 2 (Nrf2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that protect against oxidative stress resulted from a variety of stimuli including exposure to xenobiotics, and inflammation. Mitogen-activated protein kinase phosphatase-1 (Mkpl), a protein phosphatase that dephosphorylates both the phosphothreonine and phosphotyrosine residues on activated MAPKs, plays an important role in stress response and inflammatory response. This study was carried out to investigate the mechanisms of Mkp1 regulating Nrf2 and the cross-talks between the two signaling pathways. Herein, we showed that the basal and induced expressions of Nrf2 and its down stream detoxification enzymes by Butylated hydroxyanisole (BHA) or sulforaphane (SFN), activators of Nrf2, were significantly decreased in Mkp1-/- mice, indicating Mkpl involved in the activation of Nrf2 signalling pathway in vivo. Interestingly, BHA and SFN also increased the expression of Mkp1 in the liver from the WT mice but not Nrf2-/- mice, suggesting Nrf2 can also regulate the expression of Mkp1. Furthermore, when the mice were challenged with lipopolysaccharide (LPS), the expression of Nrf2 was induced in the lung from the WT mice but not Mkp1-/- mice, while the induction of Mkpl by LPS was attenuated inNr-/- mice. In addition, immunoprecipitation using antibodies against Mkpl or Nrf2 revealed the interaction between Mkpl and Nrf2. In summary, our study revealed a novel mechanism of Nrf2 regulation by Mkp1.