TIPE2 suppresses atherosclerosis by exerting a protective effect on macrophages via the inhibition of the Akt signaling pathway

Li,Dan; Tan,Ying

doi:10.3892/etm.2019.7316

TIPE2 suppresses atherosclerosis by exerting a protective effect on macrophages via the inhibition of the Akt signaling pathway

Authors:
- Dan Li
- Ying Tan
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Affiliations: Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China, Department of Cardiovascular Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421000, P.R. China
Published online on: February 26, 2019 https://doi.org/10.3892/etm.2019.7316
Pages: 2937-2944
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Macrophage apoptosis and inflammation serve pivotal roles in the occurrence of atherosclerosis. However, the detailed underlying mechanism of macrophage action during atherosclerosis is poorly understood. Tumor necrosis factor‑α‑induced protein 8‑like 2 (TIPE2) is a well‑known negative regulator of the immune response. The current study assessed the association between TIPE2 and apoptosis‑associated molecules in macrophages during atherosclerosis, as well as the role of TIPE2 in macrophage inflammation. RAW264.7 macrophages were subsequently transfected with a TIPE2 expression plasmid. Following oxidized low‑density lipoprotein (oxLDL) induction (100 µg/m1) for 48 h, macrophage apoptosis was assessed via Annexin V/propidium iodide dual staining. The apoptosis‑associated factors and Akt signaling pathway‑associated factors were also evaluated via western blot analysis. The expression of inflammatory factors was determined via a reverse transcription‑quantitative polymerase chain reaction assay and western blotting. Furthermore, a transwell assay was performed to test cell invasion ability. NF‑κB phosphorylation and nuclear translocation were also assessed via western blotting. The results demonstrated that TIPE2 overexpression may promote oxLDL‑induced RAW264.7 macrophage apoptosis by inhibiting the protein kinase B (Akt) signaling pathway. Furthermore, it was demonstrated that TIPE2 significantly reduced oxLDL‑induced tumor necrosis factor alpha (TNF‑α), interleukin‑6 (IL‑6) and monocyte chemoattractant protein 1 expression (MCP‑1), and increased IL‑10 expression by suppressing NF‑κB phosphorylation and nuclear translocation in RAW264.7 macrophages. These results indicated that TIPE2 serves a protective role in oxLDL‑induced RAW264.7 macrophages, and its mechanism may partly be exerted via the inhibition of the PI3K/Akt signaling pathway and the reduction of the macrophage inflammatory response achieved via the suppression of NF‑κB signal activation.

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1	Viola J and Soehnlein O: Atherosclerosis-A matter of unresolved inflammation. Semin Immunol. 27:184–193. 2015. View Article : Google Scholar : PubMed/NCBI
2	Tabas I, García-Cardeña G and Owens GK: Recent insights into the cellular biology of atherosclerosis. J Cell Biol. 209:13–22. 2015. View Article : Google Scholar : PubMed/NCBI
3	Libby P, Ridker PM and Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature. 473:317–325. 2011. View Article : Google Scholar : PubMed/NCBI
4	Gui T, Shimokado A, Sun Y, Akasaka T and Muragaki Y: Diverse roles of macrophages in atherosclerosis: From inflammatory biology to biomarker discovery. Mediators Inflamm. 2012:6930832012. View Article : Google Scholar : PubMed/NCBI
5	Wang Y, Han Z, Fan Y, Zhang J, Chen K, Gao L, Zeng H, Cao J and Wang C: MicroRNA-9 inhibits NLRP3 inflammasome activation in human atherosclerosis inflammation cell models through the JAK1/STAT signaling pathway. Cell Physiol Biochem. 41:1555–1571. 2017. View Article : Google Scholar : PubMed/NCBI
6	Zhang E and Wu Y: MicroRNAs: Important modulators of oxLDL-mediated signaling in atherosclerosis. J Atheroscler Thromb. 20:215–227. 2013. View Article : Google Scholar : PubMed/NCBI
7	Wang H and Eitzman DT: Acute myocardial infarction leads to acceleration of atherosclerosis. Atherosclerosis. 229:18–22. 2013. View Article : Google Scholar : PubMed/NCBI
8	Libby P: Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 32:2045–2051. 2012. View Article : Google Scholar : PubMed/NCBI
9	Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, Kong L, Xu L, Hilliard B, Hu S, et al: TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell. 133:415–426. 2008. View Article : Google Scholar : PubMed/NCBI
10	Xi W, Hu Y, Liu Y, Zhang J, Wang L, Lou Y, Qu Z, Cui J, Zhang G, Liang X, et al: Roles of TIPE2 in hepatitis B virus-induced hepatic inflammation in humans and mice. Mol Immunol. 48:1203–1208. 2011. View Article : Google Scholar : PubMed/NCBI
11	Li F, Zhu X, Yang Y, Huang L and Xu J: TIPE2 alleviates systemic lupus erythematosus through regulating macrophage polarization. Cell Physiol Biochem. 38:330–339. 2016. View Article : Google Scholar : PubMed/NCBI
12	Ma Y, Liu X, Wei Z and Wang X, Wang Z, Zhong W, Li Y, Zhu F, Guo C, Zhang L and Wang X: The expression and significance of TIPE2 in peripheral blood mononuclear cells from asthmatic children. Scand J Immunol. 78:523–528. 2013. View Article : Google Scholar : PubMed/NCBI
13	Zhang Y, Wei X, Liu L, Liu S, Wang Z, Zhang B, Fan B, Yang F, Huang S, Jiang F, et al: TIPE2, a novel regulator of immunity, protects against experimental stroke. J Biol Chem. 287:32546–32555. 2012. View Article : Google Scholar : PubMed/NCBI
14	Liu R, Fan T, Geng W, Chen YH, Ruan Q and Zhang C: Negative immune regulator TIPE2 promotes M2 macrophage differentiation through the activation of PI3K-AKT signaling pathway. PLoS One. 12:e01706662017. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Follo MY, Manzoli L, Poli A, McCubrey JA and Cocco L: PLC and PI3K/Akt/mTOR signalling in disease and cancer. Adv Biol Regul. 57:10–16. 2015. View Article : Google Scholar : PubMed/NCBI
17	Liu YC, Zou XB, Chai YF and Yao YM: Macrophage polarization in inflammatory diseases. Int J Biol Sci. 10:520–529. 2014. View Article : Google Scholar : PubMed/NCBI
18	Wang Y, Wang GZ, Rabinovitch PS and Tabas I: Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages. Circ Res. 114:421–433. 2014. View Article : Google Scholar : PubMed/NCBI
19	Taleb S, Tedgui A and Mallat Z: IL-17 and Th17 cells in atherosclerosis: Subtle and contextual roles. Arterioscler Thromb Vasc Biol. 35:258–264. 2015. View Article : Google Scholar : PubMed/NCBI
20	Shao BZ, Han BZ, Zeng YX, Su DF and Liu C: The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol Sin. 37:150–156. 2016. View Article : Google Scholar : PubMed/NCBI
21	Tabas I and Bornfeldt KE: Macrophage phenotype and function in different stages of atherosclerosis. Circ Res. 118:653–667. 2016. View Article : Google Scholar : PubMed/NCBI
22	Linton MF, Babaev VR, Huang J, Linton EF, Tao H and Yancey PG: Macrophage apoptosis and efferocytosis in the pathogenesis of atherosclerosis. Circ J. 80:2259–2268. 2016. View Article : Google Scholar : PubMed/NCBI
23	Aflaki E, Balenga NA, Luschnig-Schratl P, Wolinski H, Povoden S, Chandak PG, Bogner-Strauss JG, Eder S, Konya V, Kohlwein SD, et al: Impaired Rho GTPase activation abrogates cell polarization and migration in macrophages with defective lipolysis. Cell Mol Life Sci. 68:3933–3947. 2011. View Article : Google Scholar : PubMed/NCBI
24	Martinez FO, Sica A, Mantovani A and Locati M: Macrophage activation and polarization. Front Biosci. 13:453–461. 2008. View Article : Google Scholar : PubMed/NCBI
25	Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J and Miyata M: Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci USA. 92:8264–8268. 1995. View Article : Google Scholar : PubMed/NCBI
26	Green CE, Liu T, Montel V, Hsiao G, Lester RD, Subramaniam S, Gonias SL and Klemke RL: Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization. PLoS One. 4:e67132009. View Article : Google Scholar : PubMed/NCBI
27	Mantovani A and Sica A: Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr Opin Immunol. 22:231–237. 2010. View Article : Google Scholar : PubMed/NCBI
28	Hao C, Zhang N, Geng M, Ren Q, Li Y, Wang Y, Chen YH and Liu S: Clinical significance of tipe2 protein upregulation in non-Hodgkin's Lymphoma. J Histochem Cytochem. 64:556–564. 2016. View Article : Google Scholar : PubMed/NCBI
29	Garcia JA, Ferreira HL, Vieira FV, Gameiro R, Andrade AL, Eugênio FR, Flores EF and Cardoso TC: Tumour necrosis factor-alpha-induced protein 8 (TNFAIP8) expression associated with cell survival and death in cancer cell lines infected with canine distemper virus. Vet Comp Oncol. 15:336–344. 2017. View Article : Google Scholar : PubMed/NCBI
30	Wang Z, Fayngerts S, Wang P, Sun H, Johnson DS, Ruan Q, Guo W and Chen YH: TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci USA. 109:15413–15418. 2012. View Article : Google Scholar : PubMed/NCBI
31	Lou Y, Liu S, Zhang C, Zhang G, Li J, Ni M, An G, Dong M, Liu X, Zhu F, et al: Enhanced atherosclerosis in TIPE2-deficient mice is associated with increased macrophage responses to oxidized low-density lipoprotein. J Immunol. 191:4849–4857. 2013. View Article : Google Scholar : PubMed/NCBI
32	Janabi M, Yamashita S, Hirano K, Sakai N, Hiraoka H, Matsumoto K, Zhang Z, Nozaki S and Matsuzawa Y: Oxidized LDL-induced NF-kappa B activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients. Arterioscler Thromb Vasc Biol. 20:1953–1960. 2000. View Article : Google Scholar : PubMed/NCBI
33	Zhang M, Liu J, Li M, Zhang S, Lu Y, Liang Y, Zhao K and Li Y: Insulin-like growth factor 1/insulin-like growth factor 1 receptor signaling protects against cell apoptosis through the PI3K/AKT pathway in glioblastoma cells. Exp Ther Med. 16:1477–1482. 2018.PubMed/NCBI
34	Liu S, Shen H, Xu M, Liu O, Zhao L, Liu S, Guo Z and Du J: FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-{kappa}B-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model. Am J Physiol Endocrinol Metab. 299:E351–E363. 2010. View Article : Google Scholar : PubMed/NCBI
35	Yodkeeree S, Ooppachai C, Pompimon W and Limtrakul Dejkriengkraikul P: O-methylbulbocapnine and dicentrine suppress LPS-induced inflammatory response by blocking NF-κB and AP-1 activation through inhibiting MAPKs and Akt signaling in RAW264.7 macrophages. Biol Pharm Bull. 41:1219–1227. 2018. View Article : Google Scholar : PubMed/NCBI
36	Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K and Tsatsanis C: Akt signaling pathway in macrophage activation and M1/M2 polarization. J Immunol. 198:1006–1014. 2017. View Article : Google Scholar : PubMed/NCBI
37	Biswas SK and Lewis CE: NF-κB as a central regulator of macrophage function in tumors. J Leukoc Biol. 88:877–884. 2010. View Article : Google Scholar : PubMed/NCBI
38	Timmer AM and Nizet V: IKKbeta/NF-kappaB and the miscreant macrophage. J Exp Med. 205:1255–1259. 2008. View Article : Google Scholar : PubMed/NCBI
39	Bonizzi G and Karin M: The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25:280–288. 2004. View Article : Google Scholar : PubMed/NCBI
40	Sun H, Zhuang G, Chai L, Wang Z, Johnson D, Ma Y and Chen YH: TIPE2 controls innate immunity to RNA by targeting the phosphatidylinositol 3-kinase-Rac pathway. J Immunol. 189:2768–2773. 2012. View Article : Google Scholar : PubMed/NCBI
41	Zhang Z, Liu L, Liu C, Cao S, Zhu Y and Mei Q: TIPE2 suppresses the tumorigenesis, growth and metastasis of breast cancer via inhibition of the AKT and p38 signaling pathways. Oncol Rep. 36:3311–3316. 2016. View Article : Google Scholar : PubMed/NCBI