DUSP6 Inhibitor (E/Z)-BCI Hydrochloride Attenuates Lipopolysaccharide-Induced Inflammatory Responses in Murine Macrophage Cells via Activating the Nrf2 Signaling Axis and Inhibiting the NF-κB Pathway
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Macrophages play a fundamental role in human chronic diseases such as rheumatoid arthritis, atherosclerosis, and cancer. In the present study, we demonstrated that dual-specificity phosphatase 6 (DUSP6) was upregulated by lipopolysaccharide (LPS) treatment of macrophages. (E/Z)-BCI hydrochloride (BCI) functions as a small molecule inhibitor of DUSP6, and BCI treatment inhibited DUSP6 expression in LPS-activated macrophages. BCI treatment inhibited LPS-triggered inflammatory cytokine production, including IL-1β and IL-6, but not TNF-α, and also affected macrophage polarization to an M1 phenotype. In addition, BCI treatment decreased reactive oxygen species (ROS) production and significantly elevated the levels of Nrf2. Interestingly, pharmacological inhibition of DUSP6 attenuated LPS-induced inflammatory responses was independent of extracellular signal-regulated kinase (ERK) signaling. Furthermore, BCI treatment inhibited phosphorylation of P65 and nuclear P65 expression in LPS-activated macrophages. These results demonstrated that pharmacological inhibition of DUSP6 attenuated LPS-induced inflammatory mediators and ROS production in macrophage cells via activating the Nrf2 signaling axis and inhibiting the NF-κB pathway. These anti-inflammatory effects indicated that BCI may be considered as a therapeutic agent for blocking inflammatory disorders.
KEY WORDSDusp6 inflammation LPS macrophage BCI
This study was supported by School of Stomatology, Dalian Medical University, Dalian 116044, PR China.
Fan Zhang and Bufu Tang performed the experiments. Fan Zhang analyzed the data. Zijiao Zhang and Di Xu contributed reagents, materials, and analysis tools. Fan Zhang and Bufu Tang wrote the paper. Fan Zhang edited the paper.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 1.Pullamsetti, S.S., R. Savai, W. Janssen, B.K. Dahal, W. Seeger, F. Grimminger, H.A. Ghofrani, N. Weissmann, and R.T. Schermuly. 2011. Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clinical Microbiology and Infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 17 (1): 7–14.CrossRefGoogle Scholar
- 15.Maillet, M., N.H. Purcell, M.A. Sargent, A.J. York, Bueno OF, and J.D. Molkentin. 2008. DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. The Journal of Biological Chemistry 283 (45): 31246–31255.CrossRefGoogle Scholar
- 18.Hsu, W.C., M.Y. Chen, S.C. Hsu, L.R. Huang, C.Y. Kao, W.H. Cheng, C.H. Pan, M.S. Wu, G.Y. Yu, M.S. Hung, C.M. Leu, T.H. Tan, and Y.W. Su. 2018. DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 115 (34): E8027–E8e36.CrossRefGoogle Scholar
- 22.Missinato, M.A., M. Saydmohammed, D.A. Zuppo, K.S. Rao, G.W. Opie, B. Kuhn, et al. 2018. Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration. Development (Cambridge, England) 145 (5).Google Scholar
- 31.Zhang, H., Q. Guo, C. Wang, L. Yan, Y. Fu, M. Fan, X. Zhao, and M. Li. 2013. Dual-specificity phosphatase 6 (Dusp6), a negative regulator of FGF2/ERK1/2 signaling, enhances 17beta-estradiol-induced cell growth in endometrial adenocarcinoma cell. Molecular and Cellular Endocrinology 376 (1–2): 60–69.CrossRefGoogle Scholar
- 32.Lu, J., X. Liu, Y. Liao, D. Wang, J. Chen, and S. Li. 2018. Jian-Pi-Yi-Shen formula regulates inflammatory cytokines production in 5/6 nephrectomized rats via suppression of NF-kappaB activation. Evidence-Based Complementary and Alternative Medicine : eCAM 2018: 7203547.Google Scholar
- 33.Wu, X., H. Gao, Y. Hou, J. Yu, W. Sun, Y. Wang, X. Chen, Y. Feng, Q.M. Xu, and X. Chen. 2018. Dihydronortanshinone, a natural product, alleviates LPS-induced inflammatory response through NF-kappaB, mitochondrial ROS, and MAPK pathways. Toxicology and Applied Pharmacology 355: 1–8.CrossRefGoogle Scholar