There is evidence from in vitro studies that inflammatory messengers influence the release of stress hormone via direct effects on the adrenal gland; however, the mechanisms underlying these effects in the intact organism are unknown. Here we demonstrate that systemic inflammation in rats elicited by iv injection of lipopolysaccharide results in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes are accompanied by an induced production of IL-1beta and IL-1 receptor type 1 as well as cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E(2) production in the adrenals, which also displayed prostaglandin E(2) receptors of subtypes 1 and 3 in the cortex and medulla. The IL-1beta expression was also induced by systemically administrated IL-1beta and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1beta similarly induced expression of cyclooxygenase-2, but the cyclooxygenase-2 expression was, in contrast, further enhanced by IL-1 receptor antagonist. These data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals' response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.

De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Singlenucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and 2451C>T rs532545), 5 0 -nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3 0 UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P 5 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P 5 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML. Am. J. Hematol. 88:1001Hematol. 88: -1006Hematol. 88: , 2013. V C 2013 Wiley Periodicals, Inc. IntroductionAcute myeloid leukemia (AML) is characterized by failed differentiation and uncontrolled proliferation of hematopoietic myeloid progenitor cells. With modern treatments, the majority of patients with AML obtain a complete remission (CR), but more than two-third of adult AML patients relapse and the 5-year survival rate is only 30-40%; <15% in patients above the age of 60 [1]. The most common treatment for AML currently in use is a combination of the nucleoside analog cytosine arabinoside (AraC) and an anthracycline such as daunorubicin or idarubicin, followed by consolidation chemotherapy and/or stem cell transplantation.Cytogenetic characterization of AML at diagnosis is crucial for treatment strategies and prognosis. Based on cytogenetic aberrations, patients can be stratified into high-, intermediate-, and low-risk patient groups [2,3]. However, almost half of the AML patients do not show any cytogenetic aberrations and are referred to as normal karyotype AML (NK-AML) [2]. Patients (<70 years) in this group have a 5-year overall survival (OS) of 35-40%, but this intermediate-risk group is very heterogeneous with respect to treatment response and risk of relapse [4].A number of mutations are known to predict response and outcome in the NK-AML group [5,6]. The fms-like tyrosine kinase 3 (FLT3) gene is mutated and constitutively active in about 30% of the AML patients, the m...

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We show that AraG can cause hypomethylation of DNA and induce the expression of the fetal hemoglobin gamma gene and the ABCB1 gene. We speculate that the induction of ABCB1/P-gp may occur in order to help with excretion of hemoglobin degradation products that would otherwise be toxic to the cells, and we present data supporting our theory that P-gp may be linked to the induction of hemoglobin.