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Indoleamine 2,3-dioxygenase (IDO), a catabolizing enzyme of tryptophan, is a novel immunosuppressive agent blocking T-cell activation in neoplastic cells, including acute myeloid leukemia (AML) cells. IDO inhibitors as 1-methyl tryptophan (1MT) can abrogate IDO enzymatic activity and may result in an effective immune response. Mononuclear cells (MNCs) were separated from peripheral blood of 25 AML patients and 25 normal adults. IDO expression was detected by RT-PCR and its enzymatic activity by a colorimetric method. MNCs were cultured and the effects of Adriamycin, 1MT and a mixture of both on blast and lymphocyte cell counts after 24 and 72 h were detected. IDO mRNA and activity were detected in 52% of patients and absent in normal subjects. There was a significant correlation between IDO mRNA expression and its enzymatic activity in AML. IDO activity was correlated positively with patient's ages and negatively with hemoglobin levels. There was a significant inhibition of blast cells proliferation with Adriamycin and more inhibition when combined with 1MT. The inhibition was more after 72 h more than 24 h of culture. However, using 1MT alone showed no significant inhibitory effect on blast cells, with a significant increase in lymphocyte counts. Our study confirms the role of indoleamine 2,3-dioxygenase in tumor-induced immune tolerance and points to the possible benefit of 1-methyl tryptophan as immunotherapeutic enhancing the anticancer effects of traditional chemotherapeutics.

Objective—Preeclampsia has been associated with elevated pro-inflammatory markers, increased sympathetic activity and decreased plasma volume. We hypothesized that these associations would be identified in women prior to a first pregnancy. Methods—We studied 76 healthy nulligravid subjects measuring the pro-inflammatory markers Creactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha. Plasma volume (PV) was measured in supine position and corrected for body mass index (BMI). We examined supine plasma levels of epinephrine and norepinephrine and blood pressure response to Valsalva’s maneuver to quantify sympathetic activation. We then examined the association of plasma volume and sympathetic activity with pro-inflammatory cytokines with P < 0.05 accepted for significance. Results—CRP was significantly increased in subjects with lowest PV/BMI quartile when compared to middle two quartiles and highest quartile (ANOVA, p = 0.037). We found no significant association of PV/BMI with either interleukin 6 or tumor necrosis factor alpha. Both plasma epinephrine concentration (r = 0.29, P = 0.02) and the phase II_L blood pressure response to Valsalva’s maneuver (r = 0.44, P < 0.0001) were associated with serum IL-6 concentrations. Conclusions—Low plasma volume is associated with increased CRP levels and increased sympathetic tone is linked to elevated IL-6 concentration in young non-pregnant women. These findings represent elements of a non-pregnancy phenotype that parallels the findings observed in preeclampsia and in women at risk for ischemic cardiovascular disease. This suggests that the relationships observed during preeclampsia, which have been associated with placental pathology, may predate pregnancy and be independent of placental activity.

Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases., The hormone adiponectin is produced by fat cells and has positive metabolic effects. Here, Kim et al. show that DNA methyltransferase 1 (DNMT1) represses adiponectin expression through hypermethylation of its promoter, and that inflammatory cytokines enhance DNMT1 activity in obese mice and humans.