We have previously shown that human monocyte-derived dendritic cells (DC) express indoleamine 2,3-dioxygenase (IDO), as well as several other enzymes of the kynurenine pathway at the mRNA level upon maturation. The tolerogenic mechanisms of this pathway remain unclear. Here we show that LPS-treated DC metabolize tryptophan as far as quinolinate. We found that IDO contributes to LPS and TNF-a + poly(I:C)-induced DC maturation since IDO inhibition using two different inhibitors impairs DC maturation. IDO knock-down using short-hairpin RNA also led to diminished LPSinduced maturation. In line with these results, the tryptophan-derived catabolites 3-hydroxyanthranilic acid and 3-hydroxykynurenine increased maturation of LPStreated DC. Concerning the molecular mechanisms of this effect, IDO acts as an intermediate pathway in LPS-induced production of reactive oxygen species and NF-jB activation, two processes that lead to DC maturation. Finally, we show that mature DC expand CD4 + CD25 high regulatory T cells in an IDO-dependent manner. In conclusion, we show that IDO constitutes an intermediate pathway in DC maturation leading to expansion of CD4 + CD25 high regulatory T cells.

Abstract. According to the World Health Organization, major depression will become the leading cause of disability worldwide by the year 2030. Despite extensive research into the mechanisms underlying this disease, the rate, prevalence and disease burden has been on the rise, particularly in the industrialized world. Epidemiological studies have shown biological and biochemical differences in disease characteristics and treatment responses in different age groups. Notable differences have been observed in the clinical presentation, co-prevalence with other diseases, interaction with the immune system and even in the outcome. Thus, there is an increased interest in characterizing these differences, particularly in terms of contribution of different factors, including age, cytokines and immunotherapy. Research into the possible mechanisms of these interactions may reveal novel opportunities for future pharmacotherapy. The aim of the present review is to document recent literature regarding the impact of inflammatory mechanisms on the pathophysiology of the depressive disorder.

BackgroundImmune dysfunction in breast cancer patients is well established. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that is linked with progression of cancer. IDO is overexpressed in triple-negative breast cancer (TNBC) cases.Materials and methodsWe conducted the first study to analyze IDO expression and overall survival in breast cancer cases in Pakistan. Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), and human EGF receptor 2 (HER2) was evaluated by immunohistochemistry. Formalin-fixed paraffin-embedded breast cancer tissues of 100 (TNBC, n=49 and non-TNBC, n=51) patients were obtained from Shaukat Khanum Memorial Cancer Hospital and Research Centre. IDO expression was analyzed in association with clinicopathological features and overall survival. A total of 100 patients were classified based on the ordinal IDO score variables as low, medium, and high. In addition, overall mean age and SD of patients was 48.28±11.82.ResultsImmunohistochemical analysis showed that high IDO was observed in the TNBC patients (65.3%) compared to that in the non-TNBC patients (33.3%). Multivariable analyses showed that TNBC was an independent risk factor for high IDO expression. Overall survival was also significantly associated with IDO score.ConclusionOur study showed that IDO protein expression is higher in TNBC patients (P<0.01) and may suggest its role in disease pathogenesis. TNBC might be effectively treated with IDO inhibitors. Furthermore, high IDO expression is considerably associated with overall decreased patient survival. IDO might be utilized as a potential biomarker and immunotherapeutic target in breast cancer patients.