Endothelial lipase is upregulated by interleukin-6 partly via the p38 MAPK and p65 NF-κB signaling pathways

Yue,Xin; Wu,Minghui; Jiang,Hong; Hao,Jing; Zhao,Qinghao; Zhu,Qing; Saren,Gaowa; Zhang,Yun; Zhang,Xiaoli

doi:10.3892/mmr.2016.5457

Endothelial lipase is upregulated by interleukin-6 partly via the p38 MAPK and p65 NF-κB signaling pathways

Authors:
- Xin Yue
- Minghui Wu
- Hong Jiang
- Jing Hao
- Qinghao Zhao
- Qing Zhu
- Gaowa Saren
- Yun Zhang
- Xiaoli Zhang
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Affiliations: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology & Embryology, Medical College, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: June 30, 2016 https://doi.org/10.3892/mmr.2016.5457
Pages: 1979-1985
Copyright: © Yue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

To investigate the effects of inflammatory factor interleukin (IL)‑6 on the expression of endothelial lipase (EL) and its potential signaling pathways in atherosclerosis, a primary culture of human umbilical vein endothelial cells (HUVECs) was established and treated as follows: i) Control group without any treatment; ii) recombinant human (rh)IL‑6 treatment (10 ng/ml) for 0, 4, 8, 12 and 24 h; iii) p38 mitogen‑activated protein kinases (MAPKs) inhibitor (SB203580, 10 µmol/l) pretreatment for 1 h prior to rhIL‑6 (10 ng/ml) treatment; iv) nuclear factor (NF)‑κB activation inhibitor (pyrrolidine dithiocarbamate, 10 mmol/l) pretreatment for 1 h prior to rhIL‑6 (10 ng/ml) treatment. EL levels were detected by immunocytochemical staining and western blot analysis. Proliferation of HUVECs was detected by immunostaining of proliferating cell nuclear antigen (PCNA) and an MTT assay. p38 MAPK and NF‑κB p65 levels were detected by western blotting. The results showed that rhIL‑6 treatment increased EL expression and proliferation of HUVECs. NF‑κB p65 and MAPK p38 protein levels also increased in a time‑dependent manner in HUVECs after rhIL‑6 treatment. NF‑κB inhibitor and MAPK p38 inhibitor prevented the effects of rhIL‑6 on EL expression. In conclusion, inflammatory factor IL‑6 may participate in the pathogenesis of atherosclerosis by increasing EL expression and the proliferation of endothelial cells via the p38 MAPK and NF-κB signaling pathways.

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1	Rattazzi M, Puato M, Faggin E, Bertipaglia B, Zambon A and Pauletto P: C-reactive protein and interleukin-6 in vascular disease: Culprits or passive bystanders? J Hypertens. 21:1787–1803. 2003. View Article : Google Scholar : PubMed/NCBI
2	Bernberg E, Ulleryd MA, Johansson ME and Bergström GM: Social disruption stress increases IL-6 levels and accelerates atherosclerosis in ApoE-/- mice. Atherosclerosis. 221:359–365. 2012. View Article : Google Scholar : PubMed/NCBI
3	Nishimoto N: Interleukin-6 in rheumatoid arthritis. Curr Opin Rheumatol. 18:277–281. 2006. View Article : Google Scholar : PubMed/NCBI
4	Barton BE: Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes. Expert Opin Ther Targets. 9:737–752. 2005. View Article : Google Scholar : PubMed/NCBI
5	Smolen JS and Maini RN: Interleukin-6: A new therapeutic target. Arthritis Res Ther. 8:S52006. View Article : Google Scholar : PubMed/NCBI
6	Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, Woodworth T and Gomez-Reino JJ: Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: The tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 58:2968–2980. 2008. View Article : Google Scholar : PubMed/NCBI
7	Williams SC: First IL-6-blocking drug nears approval for rare blood disorder. Nat Med. 19:11932013. View Article : Google Scholar : PubMed/NCBI
8	Jaye M, Lynch KJ, Krawiec J, Marchadier D, Maugeais C, Doan K, South V, Amin D, Perrone M and Rader DJ: A novel endothelial-derived lipase that modulates HDL metabolism. Nat Genet. 21:424–428. 1999. View Article : Google Scholar : PubMed/NCBI
9	Ishida T, Choi S, Kundu RK, Hirata K, Rubin EM, Cooper AD and Quertermous T: Endothelial lipase is a major determinant of HDL level. J Clin Invest. 111:347–355. 2003. View Article : Google Scholar : PubMed/NCBI
10	Gordon DJ and Rifkind BM: High-density lipoproteins-the clinical implications of recent studies. N Engl J Med. 321:1311–1316. 1989. View Article : Google Scholar : PubMed/NCBI
11	Broedl UC, Maugeais C, Millar JS, Jin W, Moore RE, Fuki IV, Marchadier D, Glick JM and Rader DJ: Endothelial lipase promotes the catabolism of ApoB-containing lipoproteins. Circ Res. 94:1554–1561. 2004. View Article : Google Scholar : PubMed/NCBI
12	Ishida T, Choi SY, Kundu RK, Spin J, Yamashita T, Hirata K, Kojima Y, Yokoyama M, Cooper AD and Quertermous T: Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice. J Biol Chem. 279:45085–45092. 2004. View Article : Google Scholar : PubMed/NCBI
13	Jin W, Sun GS, Marchadier D, Octtaviani E, Glick JM and Rader DJ: Endothelial cells secrete triglyceride lipase and phospholipase activities in response to cytokines as a result of endothelial lipase. Circ Res. 92:644–650. 2003. View Article : Google Scholar : PubMed/NCBI
14	Choi SY, Hirata K, Ishida T, Quertermous T and Cooper AD: Endothelial lipase: A new lipase on the block. J Lipid Res. 43:1763–1769. 2002. View Article : Google Scholar : PubMed/NCBI
15	Han J, Lee JD, Bibbs L and Ulevitch RJ: A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 265:808–811. 1994. View Article : Google Scholar : PubMed/NCBI
16	Monaco C, Andreakos E, Kiriakidis S, Mauri C, Bicknell C, Foxwell B, Cheshire N, Paleolog E and Feldmann M: Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Proc Natl Acad Sci. 101:5634–5639. 2004. View Article : Google Scholar : PubMed/NCBI
17	Annema W and Tietge UJ: Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport. Nat Rev Drug Discov. 4:193–205. 2005.
18	Badellino KO, Wolfe ML, Rielly MP and Rader DJ: Endothelial lipase concentrations are increased in metabolic syndrome and associated with coronary atherosclerosis. PLoS Med. 3:e222006. View Article : Google Scholar
19	Cai G, He G and Qi C: The association between endothelial lipase 2384A/C gene polymorphism and acute coronary syndrome in a Chinese population. Mol Biol Rep. 39:9879–9884. 2012. View Article : Google Scholar : PubMed/NCBI
20	Singaraja RR, Sivapalaratnam S, Hovingh K, Dubé MP, Castro-Perez J, Collins HL, Adelman SJ, Riwanto M, Manz J, Hubbard B, et al: The impact of partial and complete loss of function mutations in endothelial lipase on high-density lipoprotein levels and functionality in humans. Circ Cardiovasc Genet. 6:54–62. 2013. View Article : Google Scholar
21	Fang YQ, Huang L and Li AM: Correlation between the expression of endothelial lipase in CECs and the improved jeopardy score in CAD patients. Chinese Journal of Critical Care Medicine. 28:5–8. 2008.
22	Hirata K, Ishida T, Matsushita H, Tsao PS and Quertermous T: Regulated expression of endothelial cell-derived lipase. Biochem Biophys Res Commun. 272:90–93. 2000. View Article : Google Scholar : PubMed/NCBI
23	Jin W, Sun GS, Marchadier D, Octtaviani E, Glick JM and Rader DJ: Endothelial cells secrete triglyceride lipase and phospholipase activities in response to cytokines as a result of endothelial lipase. Circ Res. 92:644–650. 2003. View Article : Google Scholar : PubMed/NCBI
24	Badellino KO, Wolfe ML, Reilly MP and Rader DJ: Endothelial lipase is increased in vivo by inflammation in humans. Circulation. 117:678–685. 2008. View Article : Google Scholar : PubMed/NCBI
25	Paradis ME, Badellino KO, Rader DJ, Deshaies Y, Couture P, Archer WR, Bergeron N and Lamarche B: Endothelial lipase is associated with inflammation in humans. J Lipid Res. 47:2808–2813. 2006. View Article : Google Scholar : PubMed/NCBI
26	Yogi A, Callera GE, Aranha AB, Antunes TT, Graham D, McBride M, Dominiczak A and Touyz RM: Sphingosine-1-phosphate-induced inflammation involves receptor tyrosine kinase transactivation in vascular cells: Upregulation in hypertension. Hypertension. 57:809–818. 2011. View Article : Google Scholar : PubMed/NCBI
27	Gerthoffer WT: Mechanisms of vascular smooth muscle cell migration. Circ Res. 100:607–621. 2007. View Article : Google Scholar : PubMed/NCBI
28	Jacobsen JC, Mulvany MJ and Holstein-Rathlou NH: A mechanism for arteriolar remodeling based on maintenance of smooth muscle cell activation. Am J Physiol Regul Integr Comp Physiol. 294:R1379–R1389. 2008. View Article : Google Scholar : PubMed/NCBI
29	Paravicini TM, Montezano AC, Yusuf H and Touyz RM: Activation of vascular p38 MAPK by mechanical stretch is independent of c-Src and NADPH oxidase: Influence of hypertension and angiotensin II. J Am Soc Hypertension. 6:169–178. 2012. View Article : Google Scholar
30	Oeckinghaus A and Ghosh S: The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 1:a0000342009. View Article : Google Scholar
31	Brand K, Page S, Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C and Baeuerle PA: Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest. 97:1715–1722. 1996. View Article : Google Scholar : PubMed/NCBI
32	Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T and Cybulsky MI: The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci USA. 97:9052–9057. 2000. View Article : Google Scholar : PubMed/NCBI
33	Cao Y, Zhou X, Liu H, Zhang Y, Yu X and Liu C: The NF-κB pathway: Regulation of the instability of atherosclerotic plaques activated by Fg, Fb and FDPs. Mol Cell Biochem. 383:29–37. 2013. View Article : Google Scholar : PubMed/NCBI