Leucine-rich glioma inactivated 3: Integrative analyses support its role in the cytokine network

Kim,Hyun A; Kwon,Nyoun Soo; Baek,Kwang Jin; Kim,Dong-Seok; Yun,Hye-Young

doi:10.3892/ijmm.2017.2988

Leucine-rich glioma inactivated 3: Integrative analyses support its role in the cytokine network

Authors:
- Hyun A Kim
- Nyoun Soo Kwon
- Kwang Jin Baek
- Dong-Seok Kim
- Hye-Young Yun
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Affiliations: Department of Biochemistry, Chung-Ang University, College of Medicine, Seoul 06974, Republic of Korea
Published online on: May 15, 2017 https://doi.org/10.3892/ijmm.2017.2988
Pages: 251-259

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Abstract

Leucine-rich glioma inactivated (LGI)3 is a secreted protein member of LGI family. We previously reported that LGI3 was upregulated in adipose tissues from obese mice and suppressed adipogenesis through its receptor, a disintegrin and metalloproteinase domain-containing protein 23 (ADAM23). We demonstrated that LGI3 regulated tumor necrosis factor-α and adiponectin, and proposed that LGI3 may be a pro-inflammatory adipokine involved in adipose tissue inflammation. In this study, we analyzed adipokine and cytokine profiles in LGI3 knockout mice and demonstrated that multiple factors were increased or decreased in the adipose tissues and plasma of the LGI3 knockout mice. Phosphoprotein array analysis revealed increases in the phosphorylation levels of Akt, AMP-activated protein kinase (AMPK), Bad, extracellular signal-regulated kinase (Erk)1/2, glycogen synthase kinase 3α (GSK3α), phosphatase and tensin homolog (PTEN) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in the LGI3-treated 3T3-L1 pre-adipocytes. Treatment with LGI3 increased the expression of various inflammatory genes in pre-adipocytes, adipocytes and macrophages. Integrative functional enrichment analysis for all LGI3-regulated gene products suggested their involvement in a number of biological processes, including cancer, inflammatory response, response to wounding, as well as cell proliferation and differentiation. Protein interaction network analysis of LGI3‑regulated gene products revealed that 94% of the gene products formed a cluster of interaction networks. Taken together, these results support the critical involvement of LGI3 in the cytokine network by interplaying with multiple adipokines, cytokines and signaling proteins.

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1	Lee SE, Lee AY, Park WJ, Jun DH, Kwon NS, Baek KJ, Kim YG and Yun HY: Mouse LGI3 gene: expression in brain and promoter analysis. Gene. 372:8–17. 2006. View Article : Google Scholar : PubMed/NCBI
2	Park WJ, Lee SE, Kwon NS, Baek KJ, Kim DS and Yun HY: Leucine-rich glioma inactivated 3 associates with syntaxin 1. Neurosci Lett. 444:240–244. 2008. View Article : Google Scholar : PubMed/NCBI
3	Park WJ, Lim YY, Kwon NS, Baek KJ, Kim DS and Yun HY: Leucine-rich glioma inactivated 3 induces neurite outgrowth through Akt and focal adhesion kinase. Neurochem Res. 35:789–796. 2010. View Article : Google Scholar : PubMed/NCBI
4	Kim HA, Park WJ, Jeong HS, Lee HE, Lee SH, Kwon NS, Baek KJ, Kim DS and Yun HY: Leucine-rich glioma inactivated 3 regulates adipogenesis through ADAM23. Biochim Biophys Acta. 1821:914–922. 2012. View Article : Google Scholar : PubMed/NCBI
5	Lee SH, Jeong YM, Kim SY, Jeong HS, Park KC, Baek KJ, Kwon NS, Yun HY and Kim DS: Ultraviolet B-induced LGI3 secretion protects human keratinocytes. Exp Dermatol. 21:716–718. 2012. View Article : Google Scholar : PubMed/NCBI
6	Jeong HS, Jeong YM, Kim J, Lee SH, Choi HR, Park KC, Kim BJ, Baek KJ, Kwon NS, Yun HY, et al: Leucine-rich glioma inactivated 3 is a melanogenic cytokine in human skin. Exp Dermatol. 23:600–602. 2014. View Article : Google Scholar : PubMed/NCBI
7	Jeong YM, Park WJ, Kim MK, Baek KJ, Kwon NS, Yun HY and Kim DS: Leucine-rich glioma inactivated 3 promotes HaCaT keratinocyte migration. Wound Repair Regen. 21:634–640. 2013. View Article : Google Scholar : PubMed/NCBI
8	Kim HA, Kwon NS, Baek KJ, Kim DS and Yun HY: Leucine-rich glioma inactivated 3 associates negatively with adiponectin. Cytokine. 62:206–209. 2013. View Article : Google Scholar : PubMed/NCBI
9	Kim HA, Kwon NS, Baek KJ, Kim DS and Yun HY: Leucine-rich glioma inactivated 3 and tumor necrosis factor-α regulate mutually through NF-κB. Cytokine. 72:220–223. 2015. View Article : Google Scholar : PubMed/NCBI
10	Huang W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar
11	Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al: STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43:D447–D452. 2015. View Article : Google Scholar
12	Lopes CT, Franz M, Kazi F, Donaldson SL, Morris Q and Bader GD: Cytoscape web: an interactive web-based network browser. Bioinformatics. 26:2347–2348. 2010. View Article : Google Scholar : PubMed/NCBI
13	Antonopoulos AS, Margaritis M, Coutinho P, Shirodaria C, Psarros C, Herdman L, Sanna F, De Silva R, Petrou M, Sayeed R, et al: Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes. 64:2207–2219. 2015. View Article : Google Scholar : PubMed/NCBI
14	Du J, Fan LM, Mai A and Li JM: Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice. Br J Pharmacol. 170:1064–1077. 2013. View Article : Google Scholar : PubMed/NCBI
15	Fernandez-Twinn DS, Blackmore HL, Siggens L, Giussani DA, Cross CM, Foo R and Ozanne SE: The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation. Endocrinology. 153:5961–5971. 2012. View Article : Google Scholar : PubMed/NCBI
16	Hotamisligil GS, Shargill NS and Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 259:87–91. 1993. View Article : Google Scholar : PubMed/NCBI
17	Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, et al: MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 116:1494–1505. 2006. View Article : Google Scholar : PubMed/NCBI
18	Kapur S, Marcotte B and Marette A: Mechanism of adipose tissue iNOS induction in endotoxemia. Am J Physiol. 276:E635–E641. 1999.PubMed/NCBI
19	Pietiläinen KH, Kannisto K, Korsheninnikova E, Rissanen A, Kaprio J, Ehrenborg E, Hamsten A and Yki-Järvinen H: Acquired obesity increases CD68 and tumor necrosis factor-alpha and decreases adiponectin gene expression in adipose tissue: a study in monozygotic twins. J Clin Endocrinol Metab. 91:2776–2781. 2006. View Article : Google Scholar : PubMed/NCBI
20	Ronis MJ, Sharma N, Vantrease J, Borengasser SJ, Ferguson M, Mercer KE, Cleves MA, Gomez-Acevedo H and Badger TM: Female mice lacking p47^phox have altered adipose tissue gene expression and are protected against high fat-induced obesity. Physiol Genomics. 45:351–366. 2013. View Article : Google Scholar : PubMed/NCBI
21	Sindhu S, Thomas R, Shihab P, Sriraman D, Behbehani K and Ahmad R: Obesity is a positive modulator of IL-6R and IL-6 expression in the subcutaneous adipose tissue: significance for metabolic inflammation. PLoS One. 10:e01334942015. View Article : Google Scholar : PubMed/NCBI
22	Uchida K, Satoh M, Inoue G, Onuma K, Miyagi M, Iwabuchi K and Takaso M: CD11c(+) macrophages and levels of TNF-α and MMP-3 are increased in synovial and adipose tissues of osteoarthritic mice with hyperlipidaemia. Clin Exp Immunol. 180:551–559. 2015. View Article : Google Scholar : PubMed/NCBI
23	Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL and Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 112:1796–1808. 2003. View Article : Google Scholar : PubMed/NCBI
24	Rossi MR, Huntoon K and Cowell JK: Differential expression of the LGI and SLIT families of genes in human cancer cells. Gene. 356:85–90. 2005. View Article : Google Scholar : PubMed/NCBI
25	West NR, McCuaig S, Franchini F and Powrie F: Emerging cytokine networks in colorectal cancer. Nat Rev Immunol. 15:615–629. 2015. View Article : Google Scholar : PubMed/NCBI
26	Lippitz BE: Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 14:e218–e228. 2013. View Article : Google Scholar : PubMed/NCBI
27	Dalamaga M, Diakopoulos KN and Mantzoros CS: The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 33:547–594. 2012. View Article : Google Scholar : PubMed/NCBI
28	Choi JH, Banks AS, Estall JL, Kajimura S, Boström P, Laznik D, Ruas JL, Chalmers MJ, Kamenecka TM, Blüher M, et al: Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 466:451–456. 2010. View Article : Google Scholar : PubMed/NCBI
29	Huang XF and Chen JZ: Obesity, the PI3K/Akt signal pathway and colon cancer. Obes Rev. 10:610–616. 2009. View Article : Google Scholar : PubMed/NCBI
30	Kaur P, Reis MD, Couchman GR, Forjuoh SN, Greene JF and Asea A: SERPINE 1 links obesity and diabetes: a pilot study. J Proteomics Bioinform. 3:191–199. 2010. View Article : Google Scholar : PubMed/NCBI
31	Kumar PA, Chitra PS, Lu C, Sobhanaditya J and Menon R: Growth hormone (GH) differentially regulates NF-kB activity in preadipocytes and macrophages: implications for GH's role in adipose tissue homeostasis in obesity. J Physiol Biochem. 70:433–440. 2014. View Article : Google Scholar : PubMed/NCBI
32	Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Brönneke HS, et al: Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol. 15:423–430. 2014. View Article : Google Scholar : PubMed/NCBI
33	Pal A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, Lachlan KL, Cooper NS, Linden H, Levy JC, Wakelam MJ, et al: PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med. 367:1002–1011. 2012. View Article : Google Scholar : PubMed/NCBI
34	Yokoyama M, Okada S, Nakagomi A, Moriya J, Shimizu I, Nojima A, Yoshida Y, Ichimiya H, Kamimura N, Kobayashi Y, et al: Inhibition of endothelial p53 improves metabolic abnor-malities related to dietary obesity. Cell Reports. 7:1691–1703. 2014. View Article : Google Scholar