NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) are cytosolic enzymes that catalyze metabolic reduction of quinones and derivatives. NQO1-null and NQO2-null mice were generated that showed decreased lymphocytes in peripheral blood, myeloid hyperplasia, and increased sensitivity to skin carcinogenesis. In this report, we investigated the in vivo role of NQO1 and NQO2 in immune response and autoimmunity. Both NQO1-null and NQO2-null mice showed decreased B-cells in blood, lower germinal center response, altered B cell homing, and impaired primary and secondary immune responses. NQO1-null and NQO2-null mice also showed susceptibility to autoimmune disease as revealed by decreased apoptosis in thymocytes and predisposition to collagen-induced arthritis. Further experiments showed accumulation of NADH and NRH, cofactors for NQO1 and NQO2, indicating altered intracellular redox status. The studies also demonstrated decreased expression and lack of activation of immune-related factor NF-B. Microarray analysis showed altered chemokines and chemokine receptors. These results suggest that the loss of NQO1 and NQO2 leads to altered intracellular redox status, decreased expression and activation of NF-B, and altered chemokines. The results led to the conclusion that NQO1 and NQO2 are endogenous factors in the regulation of immune response and autoimmunity.Quinone oxidoreductases (NQO1 and NQO2) 2 are cytosolic flavoproteins that catalyze two-electron metabolic reduction and detoxification of quinones and derivatives (1, 2). This leads to protection of cells against oxidative stress and neoplasia. However, in some cases, especially in the absence of conjugating reactions, the hydroquinones undergo oxidation to generate reactive oxygen species causing damage to cells (1, 2). NQO1-null and NQO2-null mice lacking respective gene expression showed alterations in intracellular redox status, myeloid hyperplasia, and higher susceptibility to skin carcinogenesis (3-7). Both NQO1-null and NQO2-null mice demonstrated lower expression and induction of tumor suppressor p53 (7,8). NQO1 protects p53 from ubiquitin-independent 20 S proteasomal degradation (9).A cytosine to thymidine (C 3 T) polymorphism in exon 6 of human NQO1 gene produces a proline to serine (P187S) substitution that destabilizes the protein (10, 11). Individuals carrying both mutated genomic alleles are completely lacking in NQO1 activity, whereas heterozygous individuals with one mutated allele have low-to-intermediate NQO1 activity as compared with wild-type individuals (12). Approximately 2-4% human individuals are homozygous and 20 -25% are heterozygous for this mutation (13-16).The roles of genetic factors in immune deficiency and autoimmune diseases have been recognized for decades (17). B cells play a key role in regulation of immune system. B cells produce antibodies, provide support to other mononuclear cells, and contribute directly to inflammatory pathways (18). Impaired B cell production, maturation, homing, and activation are...

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