Interleukin-10 (IL-10) is a classic anti-inflammatory cytokine that exerts its effects via the receptor complexes IL-10RA and IL-10RB. Loss of IL-10RB results in many diseases. Moreover, IL-10RB is closely associated with neuronal survival and synaptic formation. However, the regulation of IL-10RB gene expression remains elusive.
Objective:
To investigate whether the expression of IL-10RB gene is increased in brain of Alzheimer’s disease (AD) and its transcriptional regulation.
Methods:
We examined the gene expression of AD patient brain from public database and detected the protein expression of AD model mouse brain by western blot. We constructed a variety of reporter gene plasmids with different lengths or mutation sites, tested the promoter activity and defined the functional region of the promoter with the luciferase reporter assay. The protein-DNA binding between transcription factors and the promoter was analyzed using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA).
Results:
We found that the IL-10RB is elevated in the brain of AD patient and AD model mice. The minimal promoter of the IL-10RB gene is located in the –90 to +51 bp region (relative to the transcriptional start site) and is sufficient for high-level expression of the IL-10RB gene. Transcription factors Sp8 and Sp9 bind to the IL-10RB promoter in vitro. The overexpression or knockdown of Sp8 and Sp9 affected the IL-10RB promoter activity and its gene expression.
Conclusion:
Our study functionally characterized the promoter of the IL-10RB gene and demonstrated that Sp8 and Sp9 regulated its expression.
ScheltensP, BlennowK, BretelerMM, de StrooperB, FrisoniGB, SallowayS, Van der FlierWM (2016) Alzheimer’s disease. Lancet388, 505–517.
2.
HardyJ, SelkoeDJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science297, 353–356.
3.
SelkoeDJ, HardyJ (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med8, 595–608.
4.
McGeerPL, McGeerEG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: Implications for therapy. Acta Neuropathol126, 479–497.
5.
FerrettiMT, CuelloAC (2011) Does a pro-inflammatory process precede Alzheimer’s disease and mild cognitive impairment? . Curr Alzheimer Res8, 164–174.
6.
RansohoffRM (2016) How neuroinflammation contributes to neurodegeneration. Science353, 777–783.
7.
StreitWJ, BraakH, XueQS, BechmannI (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol118, 475–485.
8.
SwardfagerW, LanctôtK, RothenburgL, WongA, CappellJ, HerrmannN (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry68, 930–941.
9.
VladSC, MillerDR, KowallNW, FelsonDT (2008) Protective effects of NSAIDs on the development of Alzheimer disease. Neurology70, 1672–1677.
10.
MooreKW, de Waal MalefytR, CoffmanRL, O’GarraA (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol19, 683–765.
11.
FreiK, LinsH, SchwerdelC, FontanaA (1994) Antigen presentation in the central nervous system. The inhibitory effect of IL-10 on MHC class II expression and production of cytokines depends on the inducing signals and the type of cell analyzed. J Immunol152, 2720–2728.
12.
QianL, HongJS, FloodPM (2006) Role of microglia in inflammation-mediated degeneration of dopaminergic neurons: Neuroprotective effect of interleukin 10. J Neural Transm Suppl367–371.
13.
SzczepanikAM, FunesS, PetkoW, RingheimGE (2001) IL-4, IL-10 and IL-13 modulate A beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol113, 49–62.
14.
LynchAM, WalshC, DelaneyA, NolanY, CampbellVA, LynchMA (2004) Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10–a role for IL-1 beta? . J Neurochem88, 635–646.
FinbloomDS, WinestockKD (1995) IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J Immunol155, 1079–1090.
19.
PestkaS, KrauseCD, SarkarD, WalterMR, ShiY, FisherPB (2004) Interleukin-10 and related cytokines and receptors. Annu Rev Immunol22, 929–979.
RompornS, HirankarnN, TangkijvanichP, KimkongI (2013) Association of IFNAR2 and IL10RB genes in chronic hepatitis B virus infection. Tissue Antigens82, 21–25.
22.
LiuY, QiG, BellantiJA, MoserR, RyffelB, ZhengSG (2020) Regulatory T cells: A potential weapon to combat COVID-19? . MedComm1, 157–164.
23.
MaY, HuangY, ZhaoS, YaoY, ZhangY, QuJ, WuN, SuJ (2021) Integrative genomics analysis reveals a 21q22.11 locus contributing risk to COVID-19. Hum Mol Genet30, 1247–1258.
24.
ParkHK, KimDH, YunDH, BanJY (2013) Association between IL10, IL10RA, and IL10RB SNPs and ischemic stroke with hypertension in Korean population. Mol Biol Rep40, 1785–1790.
25.
XiuMH, TianL, ChenS, TanYL, ChenDC, ChenJ, ChenN, De YangF, LicinioJ, KostenTR, SoaresJC, ZhangXY (2016) Contribution of IL-10 and its -592 A/C polymorphism to cognitive functions in first-episode drug-naive schizophrenia. Brain Behav Immun57, 116–124.
26.
RungeEM, IyerAK, SetterDO, KennedyFM, SandersVM, JonesKJ (2020) CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy. J Neuroinflammation17, 121.
27.
HagenG, MüllerS, BeatoM, SuskeG (1992) Cloning by recognition site screening of two novel GT box binding proteins: A family of Sp1 related genes. Nucleic Acids Res20, 5519–5525.
28.
DunahAW, JeongH, GriffinA, KimYM, StandaertDG, HerschSM, MouradianMM, YoungAB, TaneseN, KraincD (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science296, 2238–2243.
29.
LiSH, ChengAL, ZhouH, LamS, RaoM, LiH, LiXJ (2002) Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol22, 1277–1287.
30.
ChristensenMA, ZhouW, QingH, LehmanA, PhilipsenS, SongW (2004) Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Mol Cell Biol24, 865–874.
31.
DocagneF, GabrielC, LebeurrierN, LesnéS, HommetY, PlawinskiL, MackenzieET, VivienD (2004) Sp1 and Smad transcription factorsco-operate to mediate TGF-beta-dependent activation of amyloid-betaprecursor protein gene transcription. Biochem J383, 393–399.
32.
SunX, WangY, QingH, ChristensenMA, LiuY, ZhouW, TongY, XiaoC, HuangY, ZhangS, LiuX, SongW (2005) Distinct transcriptionalregulation and function of the human BACE2 and BACE1 genes. FASEB J19, 739–749.
33.
Heicklen-KleinA, GinzburgI (2000) Tau promoter confers neuronal specificity and binds Sp1 and AP-2. J Neurochem75, 1408–1418.
34.
RyuH, LeeJ, ZamanK, KubilisJ, FerranteRJ, RossBD, NeveR, RatanRR (2003) Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons. J Neurosci23, 3597–3606.
35.
ZhouX, LongJM, GeyerMA, MasliahE, KelsoeJR, Wynshaw-BorisA, ChienKR (2005) Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization. Mol Psychiatry10, 393–406.
36.
ZhouX, NieZ, RobertsA, ZhangD, SebatJ, MalhotraD, KelsoeJR, GeyerMA (2010) Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders. Hum Mol Genet19, 3797–3805.
37.
ZhouX, QyangY, KelsoeJR, MasliahE, GeyerMA (2007) Impaired postnatal development of hippocampal dentate gyrus in Sp4 null mutant mice. Genes Brain Behav6, 269–276.
38.
ZhangQ, ZhangY, WangC, XuZ, LiangQ, AnL, LiJ, LiuZ, YouY, HeM, MaoY, ChenB, XiongZQ, RubensteinJL, YangZ (2016) The zinc finger transcription factor Sp9 is required for the development of striatopallidal projection neurons. Cell Rep16, 1431–1444.
XuZ, LiangQ, SongX, ZhangZ, LindtnerS, LiZ, WenY, LiuG, GuoT, QiD, WangM, WangC, LiH, YouY, WangX, ChenB, FengH, RubensteinJL, YangZ (2018) SP8 and SP9 coordinately promoteD2-type medium spiny neuron production by activating Six3expression. Development145, dev165456.
41.
WeiS, DuH, LiZ, TaoG, XuZ, SongX, ShangZ, SuZ, ChenH, WenY, LiuG, YouY, ZhangZ, YangZ (2019) Transcription factors Sp8 and Sp9 regulate the development of caudal ganglionic eminence-derived cortical interneurons. J Comp Neurol527, 2860–2874.
42.
HoSN, HuntHD, HortonRM, PullenJK, PeaseLR (1989) Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene77, 51–59.
43.
LiuY, WangJ, HsiungGR, SongW (2020) Trehalose inhibits Aβ generation and plaque formation in Alzheimer’s disease. Mol Neurobiol57, 3150–3157.
44.
LutfallaG, HollandSJ, CinatoE, MonneronD, ReboulJ, RogersNC, SmithJM, StarkGR, GardinerK, MogensenKE (1995) Mutant U5A cells are complemented by an interferon-alpha beta receptor subunit generated by alternative processing of a new member of a cytokine receptor gene cluster. EMBO J14, 5100–5108.
45.
SpencerSD, Di MarcoF, HooleyJ, Pitts-MeekS, BauerM, RyanAM, SordatB, GibbsVC, AguetM (1998) The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med187, 571–578.
46.
WehingerJ, GouilleuxF, GronerB, FinkeJ, MertelsmannR, Weber-NordtRM (1996) IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes. FEBS Lett394, 365–370.
47.
ZhouZ, PengX, InsoleraR, FinkDJ, MataM (2009) Interleukin-10 provides direct trophic support to neurons. J Neurochem110, 1617–1627.
48.
LiB, AdamsCC, WorkmanJL (1994) Nucleosome binding by the constitutive transcription factor Sp1. J Biol Chem269, 7756–7763.
49.
BorelloU, MadhavanM, VilinskyI, FaedoA, PieraniA, RubensteinJ, CampbellK (2014) Sp8 and COUP-TF1 reciprocally regulate patterning and Fgf signaling in cortical progenitors. Cereb Cortex24, 1409–1421.
50.
BellSM, SchreinerCM, WaclawRR, CampbellK, PotterSS, ScottWJ (2003) Sp8 is crucial for limb outgrowth and neuropore closure. Proc Natl Acad Sci U S A100, 12195–12200.
