PS129. Low TNFAIP3 was normalized with antidepressant in patients with major depressive disorder

Rationale: Abnormalities in Toll-like receptors (TLRs) expression in depression have been inferred in part from observed increases in TLR4 levels in peripheral blood mononuclear cells (PBMCs) and postmortem brains of depressed and suicidal patients. Activation of the TLR4 pathway partially explained the inflammatory status in patients with major depressive disorder. However, the negative regulators for TLR4 pathway have never been investigated. Objectives: In vivo, the mRNA expression levels of negative regulation genes including SOCS1, TOLLIP, SIGIRR, MyD88, NOD2, and TNFAIP3 in PBMCs were examined in 56 patients with MDD and 35 health controls. The mRNA expression levels were assessed in parallel with a housekeeping gene using qRT-PCR before and after treatment with antidepressants. We also investigated the in vitro effects of fluoxetine on the TNFAIP3 expression. First, TNFAIP3 in human monocytes (THP-1 cell line) was measured by qRT-PCR after treated with fluoxetine (10−8-10−5 M). Second, we pretreated monocytes, which had TNFAIP3 gene knockdown, with fluoxetine before LPS-stimulation. Then, interleukin 6 (IL6) and tumor necrotic factor alpha (TNFα) were measured by qRT-PCR. Results: In vivo, TOLLIP, MyD88, NOD2 and TNFAIP3 were expressed at lower levels in patients with MDD. Only TNFAIP3 was significantly increased and normalized by treatment with antidepressants for 4 weeks. In vitro, fluoxetine could significantly increase TNFAIP3 mRNA expression in human monocyte. The suppressive effects of fluoxetine on IL-6 and TNFα decreased partially after knockdowning TNFAIP3 gene. Conclusions: These findings suggest that antidepressant treatment exerts anti-inflammatory effects in patients with MDD partially through increasing expression of TNFAIP3 gene. Further studies investigating the effects of manipulating TNFAIP3 gene on depression is needed to fully elucidate the underlying mechanism.