Langerhans-cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions containing CD207+ Langerhans cells and lymphocytes that can arise in almost any tissue and cause significant morbidity and mortality. After decades of research, the cause of LCH remains speculative. A prevailing model suggests that LCH arises from malignant transformation and metastasis of epidermal Langerhans cells. In this study, CD207+ cells and CD3+ T cells were isolated from LCH lesions to determine cell-specific gene expression. Compared to control epidermal CD207+ cells, the LCH CD207+ cells yielded 2113 differentially-expressed genes (FDR<0.01). Surprisingly, expression of many genes previously associated with LCH, including cell-cycle regulators, pro-inflammatory cytokines and chemokines were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly over-expressed in LCH CD207+ cells. Furthermore, several genes associated with immature myeloid dendritic cells were over-expressed in LCH CD207+ cells. Compared to the peripheral CD3+ cells from LCH patients, the LCH lesion CD3+ cells yielded only 162 differentially-regulated genes (FDR<0.01), and the expression profile of the LCH lesion CD3+ cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4 as well as SPP1. Results from this study support a model of LCH pathogenesis in which lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that utilizes NAD(P)H as an electron donor, catalyzing the two-electron reduction and detoxification of quinones and their derivatives. NQO1؊/؊ mice deficient in NQO1 activity and protein were generated in our laboratory (Rajendirane, V., Joseph, P., Lee, Y. H., Kimura, S., Klein-Szanto, A. J. P., Gonzalez, F. J., and Jaiswal, A. K. (1998) J. Biol. Chem. 273, 7382-7389). Mice lacking a functional NQO1 gene (NQO1؊/؊) were born normal and reproduced adeptly as the wild-type NQO1؉/؉ mice. In the present report, we show that NQO1؊/؊ mice exhibit significantly lower levels of abdominal adipose tissue as compared with the wild-type mice. The NQO1؊/؊ mice showed lower blood levels of glucose, no change in insulin, and higher levels of triglycerides, -hydroxy butyrate, pyruvate, lactate, and glucagon as compared with wild-type mice. Insulin tolerance test demonstrated that the NQO1؊/؊ mice are insulin resistant. The NQO1؊/؊ mice livers also showed significantly higher levels of triglycerides, lactate, pyruvate, and glucose. The liver glycogen reserve was found decreased in NQO1؊/؊ mice as compared with wild-type mice. The livers and kidneys from NQO1؊/؊ mice also showed significantly lower levels of pyridine nucleotides but an increase in the reduced/oxidized NAD(P)H: NAD(P) ratio. These results suggested that loss of NQO1 activity alters the intracellular redox status by increasing the concentration of NAD(P)H. This leads to a reduction in pyridine nucleotide synthesis and reduced glucose and fatty acid metabolism. The alterations in metabolism due to redox changes result in a significant reduction in the amount of abdominal adipose tissue. NAD(P)H:quinone oxidoreductase 1 (NQO1)1 is a 274-amino acid flavoprotein that catalyzes the two-electron reduction and detoxification of quinones and their derivatives (1-3). The cytosolic NQO1 activities, purified from rat liver and human adipose tissue, have been characterized and cloned (1-3).NQO1 utilizes both NADH and NADPH as electron donors (1-3). The two-electron reduction of quinones does not result in the formation of free radicals (semiquinones) and highly reactive oxygen species, hence protecting cells against the adverse effects of quinones and their derivatives (1-3). As a protective agent, NQO1 activity has been shown to prevent the formation of highly reactive quinone metabolites (4), detoxify benzo-(a)pyrene quinone (5), and reduce chromium (VI) toxicity (6). Recently, NQO1 was also shown to reduce benzo(a)pyrene and benzo(a)pyrene quinone induced mutagenicity (7,8).NQO1 activity is present in all tissues but at different levels (1-3). Various investigators have observed large variations in NQO1 activity between individuals, in different tissues from the same individual, and between normal/tumor tissues (1-3). It is generally accepted that tumor tissues and cells of hepatic and colonic origin express higher levels of NQO1, as compared with normal tissues and cells of similar origins (1-3). The normal tissue...
Dihydronicotinamide riboside (NRH):quinone oxidoreductase 2 (NQO2) is a flavoenzyme that catalyzes the reductive metabolism of quinones. To examine the in vivo role of NQO2, NQO2-null (NQO2؊/؊) mice were generated using targeted gene disruption. Mice lacking NQO2 gene expression showed no detectable developmental abnormalities and were indistinguishable from wild-type (NQO2؉/؉) mice. However, NQO2-null mice exhibited myeloid hyperplasia of the bone marrow and increased neutrophils, basophils, eosinophils, and platelets in the peripheral blood. Decreased apoptosis of bone marrow cells and circulating granulocytes contributed to myeloid hyperplasia and hyperactivity of bone marrow in NQO2-null mice. The hematological changes in NQO2؊/؊ mice were specifically associated with loss of the NQO2 gene because histological analysis of various tissues including spleen, thymus, blood cultures, and urine analysis demonstrated no sign of infection. NQO2-null mice also demonstrated decreased toxicity when exposed to menadione or menadione with NRH. These results establish a role for NQO2 in protection against myelogenous hyperplasia and in metabolic activation of menadione, leading to hepatic toxicity. The NQO2-null mice are a model for NQO2 deficiency in humans and can be used to determine the role of this enzyme in sensitivities to toxicity and carcinogenesis.
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