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Sex Differences of NOD2 and TOLLIP in Patients with Major Depressive Disorder and Human Volunteers: Role of Androgen and Androgen Receptor

Author(s): I-Na Lee, Tiao-Lai Huang, Ya-Ling Huang, Yi-Yung Hung, Hong-Yo Kang



Toll-like receptor (TLR) -4 mRNA expression is higher in the acute stage of major depressive disorder (MDD) compared with healthy controls. Some previous studies showed that higher TLR-4 expression in male than in female. However, the result is opposite to the higher prevalence of MDD in female. Here, we sought to explore the biological sex difference in mRNA expression levels of negative regulators of the TLR-4 pathway to provide some reasonable explanations.


We obtained peripheral blood mononuclear cells (PBMCs) from 100 patients with MDD and 53 healthy controls and used quantitative reverse transcription-polymerase chain reaction analysis for negative regulators of TLR 4 signaling studies. For androgen effect on the TLR regulator expression, we used the embryonic mouse hippocampal cell line (mHippoE-14), dihydrotestosterone as androgen receptor agonist, and flutamide as an antagonist.


Among healthy controls, PBMCs from males had significantly higher TOLLIP and NOD2 mRNA levels than those from females. By contrast, mRNA for TOLLIP, but not NOD2, was higher in males than females in MDD. In addition, NOD2 and AR mRNAs were found to be lower in male MDD patients than in male healthy controls. Experiments using mHippoE-14 showed that inhibition of AR signaling with the antagonist flutamide suppressed NOD2 expression, whereas treatment AR signaling with the agonist dihydrotestosterone and antagonist flutamide could not increase NOD2 expression.


TOLLIP and NOD2, negative regulators for TLR-4 pathway, are significantly higher in male than female in health control. The difference in NOD2 disappeared in patients with MDD. The decrease of NOD2 mRNA expression is associated with androgen receptor.

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