title: TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder.
abstract: Inflammation and abnormalities in Toll-like receptor (TLR) expression and activation have been linked to major depressive disorder (MDD). However, negative regulators of TLR pathways have not been previously investigated in this context. Here, we sought to investigate the association of depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17), with mRNA expression levels of negative regulators of the TLR pathway, including SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2 and TNFAIP3, in peripheral blood mononuclear cells (PBMCs) from 100 patients with MDD and 53 healthy controls, before and after treatment with antidepressants. Positive regulators of the TLR4 pathway, including Pellino 1, TRAF6 and IRAK1, were also investigated. Among all patients, MyD88s, and TNFAIP3 mRNAs were expressed at lower levels in PBMCs from patients with MDD. Multiple linear regression analyses revealed that TNFAIP3 mRNA expression before treatment was inversely correlated with severity of depression and effectively predicted improvement in HAMD-17 scores. Among 79 treatment-completers, only TNFAIP3 mRNA was significantly increased by treatment with antidepressants for 4 weeks. Treatment of human monocytes (THP-1) and mouse microglia (SIM-A9) cell lines with fluoxetine significantly increased TNFAIP3 mRNA expression and suppressed IL-6 levels. The suppressive effect of fluoxetine on IL-6 was attenuated by knockdown of TNFAIP3 expression. These findings suggest that both dysfunction of the negative regulatory system in patients with MDD and antidepressant treatment exert anti-inflammatory effects, at least in part through increased expression of the TNFAIP3 gene. They also indicate that modulating expression of the TNFAIP3 gene to rebalance TLR-mediated inflammatory signaling may be potential therapeutic strategy for treating MDD.
authors.affiliation: Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan, ROC; Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan, ROC.
authors.forename: Yi-Yung
authors.initials: YY
authors.lastname: Hung
authors.affiliation: Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan, ROC.
authors.forename: Chin-Chuen
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan, ROC; Center for Menopause and Reproductive Medicine Research and Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC. Electronic address: a540520@adm.cgmh.org.
authors.forename: Hong-Yo
authors.initials: HY
authors.lastname: Kang
authors.affiliation: Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan, ROC.
authors.forename: Tiao-Lai
authors.initials: TL
authors.lastname: Huang
mesh_terms: D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011237:Predictive Value of Tests; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000032:analysis / Q000235:genetics*
chemical_list: D000928:Antidepressive Agents; D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D005473:Fluoxetine; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: Antidepressants; Inflammation; Innate immunity; Major depressive disorder; Negative regulation; Toll-like receptor