Analysis of genes linked to depressive‑like behaviors in interleukin‑18‑deficient mice: Gene expression profiles in the brain

Yamanishi,Kyosuke; Hashimoto,Takuya; Miyauchi,Masahiro; Mukai,Keiichiro; Ikubo,Kaoru; Uwa,Noriko; Watanabe,Yuko; Ikawa,Takashi; Okuzaki,Daisuke; Okamura,Haruki; Yamanishi,Hiromichi; Matsunaga,Hisato

doi:10.3892/br.2019.1259

Analysis of genes linked to depressive‑like behaviors in interleukin‑18‑deficient mice: Gene expression profiles in the brain

Authors:
- Kyosuke Yamanishi
- Takuya Hashimoto
- Masahiro Miyauchi
- Keiichiro Mukai
- Kaoru Ikubo
- Noriko Uwa
- Yuko Watanabe
- Takashi Ikawa
- Daisuke Okuzaki
- Haruki Okamura
- Hiromichi Yamanishi
- Hisato Matsunaga
View Affiliations

Affiliations: Department of Psychoimmunology, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan, Department of Neuropsychiatry, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan, Hirakata General Hospital for Developmental Disorders, Hirakata, Osaka 573‑0122, Japan, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565‑0871, Japan
Published online on: November 25, 2019 https://doi.org/10.3892/br.2019.1259
Pages: 3-10

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Interleukin (IL)‑18 is an interferon γ‑inducing inflammatory cytokine associated with function of the immune system and other physiological functions. IL‑18‑deficient (Il18‑/‑) mice exhibit obesity, dyslipidemia, non‑alcoholic steatohepatitis and depressive‑like behavioral changes. Therefore, IL‑18 has a number of important roles associated with immunity, energy homeostasis and psychiatric conditions. In the present study, gene expression in the brains of Il18‑/‑ mice was analyzed to identify genes associated with the depressive‑like behaviors and other impairments displayed by Il18‑/‑ mice. Using whole genome microarray analysis, gene expression patterns in the brains of Il18+/+ and Il18‑/‑ mice at 6 and 12 weeks of age were examined and compared. Subsequently, genes were categorized using Ingenuity® Pathway Analysis (IPA). At 12 weeks of age, 2,805 genes were identified using microarray analysis. Genes related to ‘Major depression’ and ‘Depressive disorders’ were identified by IPA core analysis, and 13 genes associated with depression were isolated. Among these genes, fibroblast growth factor receptor 1 (Fgfr1); protein tyrosine phosphatase, non‑receptor type 1 (Ptpn1); and urocortin 3 (Ucn3) were classed as depression‑inducing and the other genes were considered depression‑suppressing genes. Subsequently, the interactions between the microarray results at 6 weeks of age and the above three depression‑inducing genes were analyzed to search for effector genes of depression at 12 weeks of age. This analysis identified cyclin D1 (Ccnd1) and NADPH oxidase 4 (Nox4). The microarray analysis results were correlated with the results of reverse transcription-quantitative PCR (RT-qPCR). Overall, the results suggest that Fgfr1, Ptpn1 and Ucn3 may be involved in depression‑like changes and Ccnd1 and Nox4 regulate these three genes in IL‑18‑deficient mice.

View Figures

View References

1	Maes M: Major depression and activation of the inflammatory response system. Adv Exp Med Biol. 461:25–46. 1999.PubMed/NCBI View Article : Google Scholar
2	Yirmiya R, Weidenfeld J, Pollak Y, Morag M, Morag A, Avitsur R, Barak O, Reichenberg A, Cohen E, Shavit Y and Ovadia H: Cytokines, ‘depression due to a general medical condition’ and antidepressant drugs. Adv Exp Med Biol. 461:283–316. 1999.PubMed/NCBI View Article : Google Scholar
3	Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK and Lanctôt KL: A meta-analysis of cytokines in major depression. Biol Psychiatry. 67:446–457. 2010.PubMed/NCBI View Article : Google Scholar
4	Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, et al: Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 378:88–91. 1995.PubMed/NCBI View Article : Google Scholar
5	Okamura H, Tsutsui H, Kashiwamura S, Yoshimoto T and Nakanishi K: Interleukin-18: A novel cytokine that augments both innate and acquired immunity. Adv Immunol. 70:281–312. 1998.PubMed/NCBI View Article : Google Scholar
6	Tsutsui H, Kayagaki N, Kuida K, Nakano H, Hayashi N, Takeda K, Matsui K, Kashiwamura S, Hada T, Akira S, et al: Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. Immunity. 11:359–367. 1999.PubMed/NCBI View Article : Google Scholar
7	Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M, et al: Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 386:619–623. 1997.PubMed/NCBI View Article : Google Scholar
8	Netea MG, Joosten LA, Lewis E, Jensen DR, Voshol PJ, Kullberg BJ, Tack CJ, van Krieken H, Kim SH, Stalenhoef AF, et al: Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat Med. 12:650–656. 2006.PubMed/NCBI View Article : Google Scholar
9	Yamanishi K, Maeda S, Kuwahara-Otani S, Watanabe Y, Yoshida M, Ikubo K, Okuzaki D, El-Darawish Y, Li W, Nakasho K, et al: Interleukin-18-deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease and steatohepatitis. Transl Res. 173:101–114.e7. 2016.PubMed/NCBI View Article : Google Scholar
10	Yamanishi K, Mukai K, Hashimoto T, Ikubo K, Nakasho K, El-Darawish Y, Li W, Okuzaki D, Watanabe Y, Hayakawa T, et al: Physiological and molecular effects of interleukin-18 administration on the mouse kidney. J Transl Med. 16(51)2018.PubMed/NCBI View Article : Google Scholar
11	Yamanishi K, Maeda S, Kuwahara-Otani S, Hashimoto T, Ikubo K, Mukai K, Nakasho K, Gamachi N, El-Darawish Y, Li W, et al: Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia. J Transl Med. 16(314)2018.PubMed/NCBI View Article : Google Scholar
12	Yamanishi K, Doe N, Mukai K, Ikubo K, Hashimoto T, Uwa N, Sumida M, El-Darawish Y, Gamachi N, Li W, et al: Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors. Neuroscience. 408:147–160. 2019.PubMed/NCBI View Article : Google Scholar
13	Amat J, Baratta MV, Paul E, Bland ST, Watkins LR and Maier SF: Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 8:365–371. 2005.PubMed/NCBI View Article : Google Scholar
14	Hamilton JP, Siemer M and Gotlib IH: Amygdala volume in major depressive disorder: A meta-analysis of magnetic resonance imaging studies. Mol Psychiatry. 13:993–1000. 2008.PubMed/NCBI View Article : Google Scholar
15	Yamanishi K, Doe N, Sumida M, Watanabe Y, Yoshida M, Yamamoto H, Xu Y, Li W, Yamanishi H, Okamura H and Matsunaga H: Hepatocyte nuclear factor 4 alpha is a key factor related to depression and physiological homeostasis in the mouse brain. PLoS One. 10(e0119021)2015.PubMed/NCBI View Article : Google Scholar
16	Ikubo K, Yamanishi K, Doe N, Hashimoto T, Sumida M, Watanabe Y, El-Darawish Y, Li W, Okamura H, Yamanishi H and Matsunaga H: Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis. Mol Med Rep. 16:301–309. 2017.PubMed/NCBI View Article : Google Scholar
17	Yoshida M, Watanabe Y, Yamanishi K, Yamashita A, Yamamoto H, Okuzaki D, Shimada K, Nojima H, Yasunaga T, Okamura H, et al: Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the brain. Int J Mol Med. 33:887–896. 2014.PubMed/NCBI View Article : Google Scholar
18	Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K and Akira S: Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity. 8:383–390. 1998.PubMed/NCBI View Article : Google Scholar
19	Tochigi M, Iwamoto K, Bundo M, Sasaki T, Kato N and Kato T: Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains. Neurosci Res. 60:184–191. 2008.PubMed/NCBI View Article : Google Scholar
20	Tezval H, Jahn O, Todorovic C, Sasse A, Eckart K and Spiess J: Cortagine, a specific agonist of corticotropin-releasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model. Proc Natl Acad Sci USA. 101:9468–9473. 2004.PubMed/NCBI View Article : Google Scholar
21	Kang HJ, Adams DH, Simen A, Simen BB, Rajkowska G, Stockmeier CA, Overholser JC, Meltzer HY, Jurjus GJ, Konick LC, et al: Gene expression profiling in postmortem prefrontal cortex of major depressive disorder. J Neurosci. 27:13329–13340. 2007.PubMed/NCBI View Article : Google Scholar
22	Tashiro E, Maruki H, Minato Y, Doki Y, Weinstein IB and Imoto M: Overexpression of cyclin D1 contributes to malignancy by up-regulation of fibroblast growth factor receptor 1 via the pRB/E2F pathway. Cancer Res. 63:424–431. 2003.PubMed/NCBI
23	Mahadev K, Motoshima H, Wu X, Ruddy JM, Arnold RS, Cheng G, Lambeth JD and Goldstein BJ: The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol. 24:1844–1854. 2004.PubMed/NCBI View Article : Google Scholar
24	Trokovic R, Trokovic N, Hernesniemi S, Pirvola U, Vogt Weisenhorn DM, Rossant J, McMahon AP, Wurst W and Partanen J: FGFR1 is independently required in both developing mid- and hindbrain for sustained response to isthmic signals. EMBO J. 22:1811–1823. 2003.PubMed/NCBI View Article : Google Scholar
25	Stevens HE, Smith KM, Maragnoli ME, Fagel D, Borok E, Shanabrough M, Horvath TL and Vaccarino FM: Fgfr2 is required for the development of the medial prefrontal cortex and its connections with limbic circuits. J Neurosci. 30:5590–5602. 2010.PubMed/NCBI View Article : Google Scholar
26	Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, et al: Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 283:1544–1548. 1999.PubMed/NCBI View Article : Google Scholar
27	Kuperman Y, Issler O, Regev L, Musseri I, Navon I, Neufeld-Cohen A, Gil S and Chen A: Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis. Proc Natl Acad Sci USA. 107:8393–8398. 2010.PubMed/NCBI View Article : Google Scholar
28	Li C, Chen P, Vaughan J, Lee KF and Vale W: Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis. Proc Natl Acad Sci USA. 104:4206–4211. 2007.PubMed/NCBI View Article : Google Scholar
29	Kasukawa T, Masumoto KH, Nikaido I, Nagano M, Uno KD, Tsujino K, Hanashima C, Shigeyoshi Y and Ueda H: Quantitative expression profile of distinct functional regions in the adult mouse brain. PLoS One. 6(e23228)2011.PubMed/NCBI View Article : Google Scholar
30	Sawada K, Young CE, Barr AM, Longworth K, Takahashi S, Arango V, Mann JJ, Dwork AJ, Falkai P, Phillips AG and Honer WG: Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness. Mol Psychiatry. 7:484–492. 2002.PubMed/NCBI View Article : Google Scholar
31	Chen G, Wang J, Liu Z and Kornmann M: Exon III splicing of fibroblast growth factor receptor 1 is modulated by growth factors and cyclin D1. Pancreas. 37:159–164. 2008.PubMed/NCBI View Article : Google Scholar
32	Fortress AM, Schram SL, Tuscher JJ and Frick KM: Canonical Wnt signaling is necessary for object recognition memory consolidation. J Neurosci. 33:12619–12626. 2013.PubMed/NCBI View Article : Google Scholar
33	Hui J, Zhang J, Pu M, Zhou X, Dong L, Mao X, Shi G, Zou J, Wu J, Jiang D and Xi G: Modulation of GSK-3β/β-catenin signaling contributes to learning and memory impairment in a rat model of depression. Int J Neuropsychopharmacol. 21:858–870. 2018.PubMed/NCBI View Article : Google Scholar
34	Yu L, Haverty PM, Mariani J, Wang Y, Shen HY, Schwarzschild MA, Weng Z and Chen JF: Genetic and pharmacological inactivation of adenosine A2A receptor reveals an Egr-2-mediated transcriptional regulatory network in the mouse striatum. Physiol Genomics. 23:89–102. 2005.PubMed/NCBI View Article : Google Scholar
35	Krishnadas R and Cavanagh J: Depression: An inflammatory illness? J Neurol Neurosurg Psychiatry. 83:495–502. 2012.PubMed/NCBI View Article : Google Scholar
36	Khairova RA, Machado-Vieira R, Du J and Manji HK: A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol. 12:561–578. 2009.PubMed/NCBI View Article : Google Scholar
37	Liu H, Luiten PG, Eisel UL, Dejongste MJ and Schoemaker RG: Depression after myocardial infarction: TNF-α-induced alterations of the blood-brain barrier and its putative therapeutic implications. Neurosci Biobehav Rev. 37:561–572. 2013.PubMed/NCBI View Article : Google Scholar
38	Yamamoto M, Guo DH, Hernandez CM and Stranahan AM: Endothelial Adora2a activation promotes blood-brain barrier breakdown and cognitive impairment in mice with diet-induced insulin resistance. J Neurosci. 39:4179–4192. 2019.PubMed/NCBI View Article : Google Scholar