Hypomethylation of the HTR1A promoter region and high expression of HTR1A in the peripheral blood lymphocytes of patients with systemic lupus erythematosus
Restricted accessResearch articleFirst published online June, 2011
Hypomethylation of the HTR1A promoter region and high expression of HTR1A in the peripheral blood lymphocytes of patients with systemic lupus erythematosus
Abstract: The occurrence of systemic lupus erythematosus (SLE) involves a gene–environment interaction and epigenetic regulations, such as DNA methylation, may play important role in the etiology of SLE. Some neurotransmitters, such as serotonin, can regulate T- and B-cell proliferation via the 5-HT1A receptor and are involved in the pathology of SLE. The abnormal methylation of DNA has been reported in SLE, but there has been no study concerning the serotonin system. This study was conducted to explore the DNA methylation status of the promoter region of HTR1A (PR-HTR1A) and the level of HTR1A mRNA in the peripheral blood lymphocytes (PBLC) of SLE patients and healthy controls (HC). In this study, the DNA methylation status of PR-HTR1A and the level of HTR1A mRNA were detected in the PBLC of SLE patients and HC. The results showed significant hypomethylation of PR-HTR1A in SLE patients compared with HC. The patients also showed a significantly higher HTR1A mRNA level than did the controls. Relatively higher percentage of anti-histone antibodies in methylated SLE patients was found compared with unmethylated patients. Our results support the hypothesis that the hypomethylation of PR-HTR1A and overexpression of HTR1A might contribute to SLE. These results also reveal that epigenetic regulation via the serotonin system may contribute to SLE, and reveal the link between the brain and the immune system.
PetersAHSchubelerD. Methylation of histones: playing memory with DNA. Curr Opin Cell Biol2005; 17: 230–238.
2.
JanuchowskiRProkopJJagodzinskiPP. Role of epigenetic DNA alterations in the pathogenesis of systemic lupus erythematosus. J Appl Genet2004; 45: 237–248.
3.
PanYSawalhaAH. Epigenetic regulation and the pathogenesis of systemic lupus erythematosus. Transl Res2009; 153: 4–10.
4.
StricklandFMRichardsonBC. Epigenetics in human autoimmunity. Epigenetics in autoimmunity – DNA methylation in systemic lupus erythematosus and beyond. Autoimmunity2008; 41: 278–286.
5.
SawalhaAHJeffriesMWebbR. Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients. Genes Immun2008; 9: 368–378.
6.
GorelikGRichardsonB. Aberrant T cell ERK pathway signaling and chromatin structure in lupus. Autoimmun Rev2009; 8: 196–198.
7.
DengCLuQZhangZ. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum2003; 48: 746–756.
8.
SawalhaAHJeffriesM. Defective DNA methylation and CD70 overexpression in CD4+ T cells in MRL/lpr lupus-prone mice. Eur J Immunol2007; 37: 1407–1413.
9.
YungRLQuddusJChrispCEJohnsonKJRichardsonBC. Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. J Immunol1995; 154: 3025–3035.
10.
RahmanAIsenbergDA. Systemic lupus erythematosus. N Engl J Med2008; 358: 929–939.
OmdalRHusbyGMellgrenSI. Mental health status in systemic lupus erythematosus. Scand J Rheumatol1995; 24: 142–145.
13.
IshikuraRMorimotoNTanakaK. Factors associated with anxiety, depression and suicide ideation in female outpatients with SLE in Japan. Clin Rheumatol2001; 20: 394–400.
14.
HayEMBlackDHuddyA. Psychiatric disorder and cognitive impairment in systemic lupus erythematosus. Arthritis Rheum1992; 35: 411–416.
15.
AinialaHLoukkolaJPeltolaJKorpelaMHietaharjuA. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology2001; 57: 496–500.
16.
NeryFGBorbaEFHatchJPSoaresJCBonfaENetoFL. Major depressive disorder and disease activity in systemic lupus erythematosus. Compr Psychiatry2007; 48: 14–19.
17.
GaoHXCampbellSRCuiMH. Depression is an early disease manifestation in lupus-prone MRL/lpr mice. J Neuroimmunol2009; 207: 45–56.
18.
JacksonJCCrossRJWalkerRFMarkesberyWRBrooksWHRoszmanTL. Influence of serotonin on the immune response. Immunology1985; 54: 505–512.
19.
PellegrinoTCBayerBM. Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release. Neuroimmunomodulation2000; 8: 179–187.
20.
HellstrandKHermodssonS. Enhancement of human natural killer cell cytotoxicity by serotonin: role of non-T/CD16+ NK cells, accessory monocytes, and 5-HT1A receptors. Cell Immunol1990; 127: 199–214.
21.
Eugen-OlsenJAfzeliusPAndresenL. Serotonin modulates immune function in T cells from HIV-seropositive subjects. Clin Immunol Immunopathol1997; 84: 115–121.
22.
IkenKChhengSFarginAGouletACKouassiE. Serotonin upregulates mitogen-stimulated B lymphocyte proliferation through 5-HT1A receptors. Cell Immunol1995; 163: 1–9.
23.
Whitaker-AzmitiaPMDruseMWalkerPLauderJM. Serotonin as a developmental signal. Behav Brain Res1996; 73: 19–29.
24.
SavitzJLuckiIDrevetsWC. 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol2009; 88: 17–31.
25.
AuneTMGoldenHWMcGrathKM. Inhibitors of serotonin synthesis and antagonists of serotonin 1A receptors inhibit T lymphocyte function in vitro and cell-mediated immunity in vivo. J Immunol1994; 153: 489–498.
26.
AuneTMMcGrathKMSarrTBombaraMPKelleyKA. Expression of 5HT1a receptors on activated human T cells. Regulation of cyclic AMP levels and T cell proliferation by 5-hydroxytryptamine. J Immunol1993; 151: 1175–1183.
HochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725–1725.
29.
GladmanDDUrowitzMBGoldsmithCH. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum1997; 40: 809–813.
30.
BombardierCGladmanDDUrowitzMBCaronDChangCH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum1992; 35: 630–640.
31.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.
32.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50–55.
33.
FolsteinMFFolsteinSEMcHughPR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res1975; 12: 189–198.
34.
OldfieldRC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia1971; 9: 97–113.
35.
NoblePBCuttsJH. Separation of blood leukocytes by Ficoll gradient. Can Vet J1967; 8: 110–111.
36.
KanedaMOkanoMHataK. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature2004; 429: 900–903.
37.
EhrichMZollSSurSvan den BoomD. A new method for accurate assessment of DNA quality after bisulfite treatment. Nucleic Acids Res2007; 35: e29–e29.
38.
FrommerMMcDonaldLEMillarDS. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A1992; 89: 1827–1831.
39.
ClarkSJHarrisonJPaulCLFrommerM. High sensitivity mapping of methylated cytosines. Nucleic Acids Res1994; 22: 2990–2997.
ParbtaniAFramptonGYewdallVKasaiNCameronJS. Platelet and plasma serotonin in glomerulonephritis. III: The nephritis of systemic lupus erythematosus. Clin Nephrol1980; 14: 164–172.
42.
LabergeSCruikshankWWBeerDJCenterDM. Secretion of IL-16 (lymphocyte chemoattractant factor) from serotonin-stimulated CD8+ T cells in vitro. J Immunol1996; 156: 310–315.
43.
StefuljJCicin-SainLSchauensteinKJernejB. Serotonin and immune response: effect of the amine on in vitro proliferation of rat lymphocytes. Neuroimmunomodulation2001; 9: 103–108.
44.
FerriereFKhanNATroutaudDDeschauxP. Serotonin modulation of lymphocyte proliferation via 5-HT1A receptors in rainbow trout (Oncorhynchus mykiss). Dev Comp Immunol1996; 20: 273–283.
45.
SempereTCedenoNUrbinaMLimaL. 8-[3H]-hydroxy-2-(di-n-propylamino)tetralin binding sites in blood lymphocytes of rats and the modulation by mitogens and immobilization. J Neuroimmunol2003; 138: 8–16.
46.
MatsudaHUshioHGebaGPAskenasePW. Human platelets can initiate T cell-dependent contact sensitivity through local serotonin release mediated by IgE antibodies. J Immunol1997; 158: 2891–2897.
47.
StefuljJJernejBCicin-SainLRinnerISchauensteinK. mRNA expression of serotonin receptors in cells of the immune tissues of the rat. Brain Behav Immun2000; 14: 219–224.
48.
Cloez-TayaraniIKayyaliUSFanburgBLCavaillonJM. 5-HT activates ERK MAP kinase in cultured-human peripheral blood mononuclear cells via 5-HT1A receptors. Life Sci2004; 76: 429–443.
49.
MarazzitiDPalegoLDal CantoB. Presence of serotonin1A (5-HT1A) receptor mRNA without binding of [3H]-8-OH-DPAT in peripheral blood mononuclear cells. Life Sci1995; 57: 2197–2203.
50.
LeeDYHayesJJPrussDWolffeAP. A positive role for histone acetylation in transcription factor access to nucleosomal DNA. Cell1993; 72: 73–84.
51.
HassigCATongJKFleischerTC. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc Natl Acad Sci U S A1998; 95: 3519–3524.
52.
BrunsABlassSHausdorfGBurmesterGRHiepeF. Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. Arthritis Rheum2000; 43: 2307–2315.
53.
AmouraZKoutouzovSPietteJC. The role of nucleosomes in lupus. Curr Opin Rheumatol2000; 12: 369–373.
54.
HuNLongHZhaoMYinHLuQ. Aberrant expression pattern of histone acetylation modifiers and mitigation of lupus by SIRT1-siRNA in MRL/lpr mice. Scand J Rheumatol2009; 38: 464–471.
55.
van BavelCCDiekerJMullerS. Apoptosis-associated acetylation on histone H2B is an epitope for lupus autoantibodies. Mol Immunol2009; 47: 511–516.
56.
DiekerJWFransenJHvan BavelCC. Apoptosis-induced acetylation of histones is pathogenic in systemic lupus erythematosus. Arthritis Rheum2007; 56: 1921–1933.
57.
GeimanTMRobertsonKD. Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together?J Cell Biochem2002; 87: 117–125.
58.
CervoniNSzyfM. Demethylase activity is directed by histone acetylation. J Biol Chem2001; 276: 40778–40787.
59.
WekkingEM. Psychiatric symptoms in systemic lupus erythematosus: an update. Psychosom Med1993; 55: 219–228.
60.
ZhouFCPatelTDSwartzDXuYKelleyMR. Production and characterization of an anti-serotonin 1A receptor antibody which detects functional 5-HT1A binding sites. Brain Res1999; 69: 186–201.
