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Mkp-1 cross-talks with Nrf2/Ho-1 pathway protecting against intestinal inflammation
Jing Li1, Hongyan Wang2, Zhaohong Zheng1
1Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, PR China.
Abstract:
Inflammatory bowel disease (IBD) is associated with intense oxidative stress, contributes to colonic damage and tumorigenesis. Mitogen-activated protein kinase phosphatase 1 (Mkp-1) is an essential negative regulator of the innate immune response. However, its role in colitis, and its association with the nuclear factor-erythroid 2 related factor 2 (Nrf2), a master regulator of cytoprotection program against oxidative stress, in inflammatory response, is elusive. In this study, we found that increased expression of Mkp-1, Nrf2, and heme oxygenase 1 (Ho-1) was correlated in colonic tissues in patients with ulcerative colitis and Crohn's disease, as well as wild-type mice with colitis induced by dextran sodium sulfate (DSS). Mkp-1-/- mice were more susceptible to DSS-induced colitis with more severe crypt injury and inflammation. Mechanistically, directly interacting with the DIDLID motif of Nrf2, Mkp-1 increased Nrf2 stability and positively regulated the constitutive and lipopolysaccharide (LPS)-inducible Nrf2/Ho-1 expression. Conversely, upon exposure to LPS, Nrf2 activated Mkp-1 transcription through the antioxidant response elements in the promoter of Mkp-1. Our results revealed a novel link between Mkp-1 and Nrf2 signaling pathways in protecting against colonic inflammation. Mkp-1 might be a therapeutic target for IBD.
Insights
Mitogen-activated protein kinase phosphatase 1 (Mkp-1) protects against inflammatory bowel disease (IBD) by stabilizing Nrf2, a key regulator of antioxidant responses. This interaction reduces colonic damage and inflammation, suggesting Mkp-1 as a potential therapeutic target for IBD.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- Inflammatory bowel disease (IBD) involves oxidative stress, colonic damage, and tumorigenesis.
- Mitogen-activated protein kinase phosphatase 1 (Mkp-1) regulates innate immunity.
- The role of Mkp-1 in colitis and its link to Nrf2, a master regulator of cytoprotection, remain unclear.
Purpose of the Study:
- To investigate the role of Mkp-1 in colitis.
- To explore the association between Mkp-1 and Nrf2 in inflammatory responses.
- To elucidate the protective mechanisms of Mkp-1 against colonic inflammation.
Main Methods:
- Analysis of Mkp-1, Nrf2, and heme oxygenase 1 (Ho-1) expression in human IBD tissues and DSS-induced colitis mouse models.
- Assessment of colitis severity in wild-type and Mkp-1 knockout mice.
- Investigation of the molecular interaction between Mkp-1 and Nrf2 using biochemical assays.
Main Results:
- Increased Mkp-1, Nrf2, and Ho-1 expression correlated in human IBD and mouse colitis.
- Mkp-1 knockout mice exhibited heightened susceptibility to DSS-induced colitis with exacerbated inflammation and crypt injury.
- Mkp-1 enhances Nrf2 stability and positively regulates Nrf2/Ho-1 expression; Nrf2, in turn, upregulates Mkp-1 transcription.
Conclusions:
- A novel protective axis between Mkp-1 and Nrf2 signaling pathways in combating colonic inflammation was identified.
- Mkp-1 plays a crucial role in mitigating colitis severity.
- Mkp-1 emerges as a potential therapeutic target for managing inflammatory bowel disease.
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