Abstract
Interleukin (IL)-32β can act as either pro-inflammatory or anti-inflammatory cytokines with being dependent on the status of disease development. Herein, we investigated whether IL-32β overexpression changes cytokine levels and affects amyloid-beta (Aβ)-induced pro-inflammation in the brain. IL-32β transgenic (Tg) mice and non-Tg mice were intracerebroventricularly infused with Aβ1-42 once a day for 14 days, and then cognitive function was assessed by the Morris water maze test and passive avoidance test. Our data showed that IL-32β Tg mice increased memory impairment, glia activation, amyloidogenesis, and neuroinflammation. The expression of glial fibrillary acid protein (GFAP), Iba1, and β-secretase 1 (BACE1) in the cortex and hippocampus was much higher in the Aβ1-42-infused IL-32β Tg mice brain. The activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-κB) was much higher in Aβ1-42-infused IL-32β Tg mice brain. We also found that cytokines including IP-10, GM-CSF, JE, IL-13, and interferone-inducible T cell α chemoattractant (I-TAC) were elevated in Aβ1-42-infused IL-32β Tg mice brain. These results suggest that IL-32β could activate NF-κB and STAT3, and thus affect neuroinflammation as well as amyloidogenesis, leading to worsening memory impairment.
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References
Dahl CA, Schall RP, He HL, Cairns JS (1992) Identification of a novel gene expressed in activated natural killer cells and T cells. J Immunol 148(2):597–603
Kim SH, Han SY, Azam T, Yoon DY, Dinarello CA (2005) Interleukin-32: a cytokine and inducer of TNFalpha. Immunity 22(1):131–142. doi:10.1016/j.immuni.2004.12.003
Netea MG, Azam T, Ferwerda G, Girardin SE, Walsh M, Park JS, Abraham E, Kim JM, Yoon DY, Dinarello CA, Kim SH (2005) IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism. Proc Natl Acad Sci U S A 102(45):16309–16314. doi:10.1073/pnas.0508237102
Vlahopoulos S, Boldogh I, Casola A, Brasier AR (1999) Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation. Blood 94(6):1878–1889
Dinarello CA (2004) Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation. Curr Opin Pharmacol 4(4):378–385. doi:10.1016/j.coph.2004.03.010
Gabay C (2006) Interleukin-6 and chronic inflammation. Arthritis Res Ther 8 Suppl 2:S3. doi:10.1186/ar1917
Kobayashi H, Huang J, Ye F, Shyr Y, Blackwell TS, Lin PC (2010) Interleukin-32beta propagates vascular inflammation and exacerbates sepsis in a mouse model. PLoS One 5(3):e9458. doi:10.1371/journal.pone.0009458
Joosten LA, Netea MG, Kim SH, Yoon DY, Oppers-Walgreen B, Radstake TR, Barrera P, van de Loo FA, Dinarello CA, van den Berg WB (2006) IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc Natl Acad Sci U S A 103(9):3298–3303. doi:10.1073/pnas.0511233103
Heinhuis B, Koenders MI, van de Loo FA, Netea MG, van den Berg WB, Joosten LA (2011) Inflammation-dependent secretion and splicing of IL-32{gamma} in rheumatoid arthritis. Proc Natl Acad Sci U S A 108(12):4962–4967. doi:10.1073/pnas.1016005108
Moschen AR, Fritz T, Clouston AD, Rebhan I, Bauhofer O, Barrie HD, Powell EE, Kim SH, Dinarello CA, Bartenschlager R, Jonsson JR, Tilg H (2011) Interleukin-32: a new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis. Hepatology 53(6):1819–1829. doi:10.1002/hep.24285
Bai X, Kim SH, Azam T, McGibney MT, Huang H, Dinarello CA, Chan ED (2010) IL-32 is a host protective cytokine against Mycobacterium tuberculosis in differentiated THP-1 human macrophages. J Immunol 184(7):3830–3840. doi:10.4049/jimmunol.0901913
Shioya M, Nishida A, Yagi Y, Ogawa A, Tsujikawa T, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y, Andoh A (2007) Epithelial overexpression of interleukin-32alpha in inflammatory bowel disease. Clin Exp Immunol 149(3):480–486. doi:10.1111/j.1365-2249.2007.03439.x
Oh JH, Cho MC, Kim JH, Lee SY, Kim HJ, Park ES, Ban JO, Kang JW, Lee DH, Shim JH, Han SB, Moon DC, Park YH, Yu DY, Kim JM, Kim SH, Yoon DY, Hong JT (2011) IL-32gamma inhibits cancer cell growth through inactivation of NF-kappaB and STAT3 signals. Oncogene 30(30):3345–3359. doi:10.1038/onc.2011.52
Choi J, Bae S, Hong J, Ryoo S, Jhun H, Hong K, Yoon D, Lee S, Her E, Choi W, Kim J, Azam T, Dinarello CA, Kim S (2010) Paradoxical effects of constitutive human IL-32{gamma} in transgenic mice during experimental colitis. Proc Natl Acad Sci U S A 107(49):21082–21086. doi:10.1073/pnas.1015418107
Yun HM, Oh JH, Shim JH, Ban JO, Park KR, Kim JH, Lee DH, Kang JW, Park YH, Yu D, Kim Y, Han SB, Yoon DY, Hong JT (2013) Antitumor activity of IL-32beta through the activation of lymphocytes, and the inactivation of NF-kappaB and STAT3 signals. Cell Death Dis 4:e640. doi:10.1038/cddis.2013.166
Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM, Lee K, Cho WG, Jung JK, Han SB, Han JY, Nam SY, Yun YW, Jeong JH, Oh KW, Hong JT (2012) Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J Neuroinflammation 9:35. doi:10.1186/1742-2094-9-35
Espinosa-Oliva AM, de Pablos RM, Herrera AJ (2013) Intracranial injection of LPS in rat as animal model of neuroinflammation. Methods Mol Biol 1041:295–305. doi:10.1007/978-1-62703-520-0_26
Yun HM, Jin P, Han JY, Lee MS, Han SB, Oh KW, Hong SH, Jung EY, Hong JT (2013) Acceleration of the development of Alzheimer’s disease in amyloid beta-infused peroxiredoxin 6 overexpression transgenic mice. Mol Neurobiol 48(3):941–951. doi:10.1007/s12035-013-8479-6
Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Al-Abed Y, Davies P, Marambaud P (2012) Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. J Neurochem 120(3):461–472. doi:10.1111/j.1471-4159.2011.07594.x
Ghosh S, Hayden MS (2008) New regulators of NF-kappaB in inflammation. Nat Rev Immunol 8(11):837–848. doi:10.1038/nri2423
Rahman A, Fazal F (2011) Blocking NF-κB: an inflammatory issue. Proc Am Thorac Soc 8(6):497–503. doi:10.1513/pats.201101-009MW
Sambamurti K, Kinsey R, Maloney B, Ge YW, Lahiri DK (2004) Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB J: Off Publ Fed Am Soc Exp Biol 18(9):1034–1036. doi:10.1096/fj.03-1378fje
Choi DY, Lee JW, Lin G, Lee YK, Lee YH, Choi IS, Han SB, Jung JK, Kim YH, Kim KH, Oh KW, Hong JT, Lee MS (2012) Obovatol attenuates LPS-induced memory impairments in mice via inhibition of NF-κB signaling pathway. Neurochem Int 60(1):68–77. doi:10.1016/j.neuint.2011.11.005
Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marie I, Maurin T, Wang L, Figueroa H, Herman M, Krishnamurthy P, Liu L, Planel E, Lau LF, Lahiri DK, Duff K (2008) Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron 57(5):680–690. doi:10.1016/j.neuron.2008.02.024
Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59(9):1381–1389
Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3):231–232. doi:10.1038/85059
Fu XY (2006) STAT3 in immune responses and inflammatory bowel diseases. Cell Res 16(2):214–219. doi:10.1038/sj.cr.7310029
Nabeshima T, Nitta A (1994) Memory impairment and neuronal dysfunction induced by beta-amyloid protein in rats. Tohoku J Exp Med 174(3):241–249
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60
Lukiw WJ (2012) NF-small ka, CyrillicB-regulated micro RNAs (miRNAs) in primary human brain cells. Exp Neurol 235(2):484–490. doi:10.1016/j.expneurol.2011.11.022
Jin P, Kim JA, Choi DY, Lee YJ, Jung HS, Hong JT (2013) Anti-inflammatory and anti-amyloidogenic effects of a small molecule, 2,4-bis(p-hydroxyphenyl)-2-butenal in Tg2576 Alzheimer’s disease mice model. J Neuroinflammation 10:2. doi:10.1186/1742-2094-10-2
Grilli M, Ribola M, Alberici A, Valerio A, Memo M, Spano P (1995) Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene. J Biol Chem 270(45):26774–26777
Bourne KZ, Ferrari DC, Lange-Dohna C, Rossner S, Wood TG, Perez-Polo JR (2007) Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides. J Neurosci Res 85(6):1194–1204. doi:10.1002/jnr.21252
Chami L, Buggia-Prevot V, Duplan E, Delprete D, Chami M, Peyron JF, Checler F (2012) Nuclear factor-kappaB regulates betaAPP and beta- and gamma-secretases differently at physiological and supraphysiological Abeta concentrations. J Biol Chem 287(29):24573–24584. doi:10.1074/jbc.M111.333054
Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, Tone Y, Tong Y, Song W (2011) Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int J Neuropsychopharmacol:1-14. doi:10.1017/S1461145711000149
Wan J, Fu AK, Ip FC, Ng HK, Hugon J, Page G, Wang JH, Lai KO, Wu Z, Ip NY (2010) Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer’s disease. J Neurosci 30(20):6873–6881. doi:10.1523/JNEUROSCI.0519-10.2010
Kitamura Y, Shimohama S, Ota T, Matsuoka Y, Nomura Y, Taniguchi T (1997) Alteration of transcription factors NF-kappaB and STAT1 in Alzheimer’s disease brains. Neurosci Lett 237(1):17–20
Fagerlund R, Melen K, Cao X, Julkunen I (2008) NF-kappaB p52, RelB and c-Rel are transported into the nucleus via a subset of importin alpha molecules. Cell Signal 20(8):1442–1451. doi:10.1016/j.cellsig.2008.03.012
Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, Korsak RA, Takeda K, Akira S, Sofroniew MV (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28(28):7231–7243. doi:10.1523/JNEUROSCI.1709-08.2008
Hashioka S, Klegeris A, Qing H, McGeer PL (2011) STAT3 inhibitors attenuate interferon-gamma-induced neurotoxicity and inflammatory molecule production by human astrocytes. Neurobiol Dis 41(2):299–307. doi:10.1016/j.nbd.2010.09.018
Caposio P, Musso T, Luganini A, Inoue H, Gariglio M, Landolfo S, Gribaudo G (2007) Targeting the NF-kappaB pathway through pharmacological inhibition of IKK2 prevents human cytomegalovirus replication and virus-induced inflammatory response in infected endothelial cells. Antiviral Res 73(3):175–184. doi:10.1016/j.antiviral.2006.10.001
Shrivastava K, Llovera G, Recasens M, Chertoff M, Gimenez-Llort L, Gonzalez B, Acarin L (2013) Temporal expression of cytokines and signal transducer and activator of transcription factor 3 activation after neonatal hypoxia/ischemia in mice. Dev Neurosci 35(2–3):212–225. doi:10.1159/000348432
Park KW, Baik HH, Jin BK (2009) IL-13-induced oxidative stress via microglial NADPH oxidase contributes to death of hippocampal neurons in vivo. J Immunol 183(7):4666–4674. doi:10.4049/jimmunol.0803392
Silbermann K, Schneider G, Grassmann R (2008) Stimulation of interleukin-13 expression by human T-cell leukemia virus type 1 oncoprotein Tax via a dually active promoter element responsive to NF-kappaB and NFAT. J Gen Virol 89(Pt 11):2788–2798. doi:10.1099/vir.0.2008/003699-0
Goto K, Chiba Y, Misawa M (2009) IL-13 induces translocation of NF-kappaB in cultured human bronchial smooth muscle cells. Cytokine 46(1):96–99. doi:10.1016/j.cyto.2008.12.021
Nakayama M, Niki Y, Kawasaki T, Takeda Y, Horiuchi K, Sasaki A, Okada Y, Umezawa K, Ikegami H, Toyama Y, Miyamoto T (2012) Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha. Arthritis Res Ther 14(3):R120. doi:10.1186/ar3850
Acknowledgments
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MISP) (No. MRC, 2008-0062275), by a grant (A101836) from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea.
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Jin A. Kim contributed equally to this work.
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Yun, HM., Kim, J.A., Hwang, C.J. et al. Neuroinflammatory and Amyloidogenic Activities of IL-32β in Alzheimer’s Disease. Mol Neurobiol 52, 341–352 (2015). https://doi.org/10.1007/s12035-014-8860-0
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DOI: https://doi.org/10.1007/s12035-014-8860-0