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Arginase Modulates NF-B Activity via a Nitric Oxide–Dependent Mechanism

Department of Pathology, University of Vermont, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Yvonne Janssen-Heininger, Ph.D., Department of Pathology, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405. E-mail: yvonne.janssen{at}uvm.edu

Abstract

NF-B is a versatile transcription factor that regulates a wide array of processes, including inflammation and survival, and plays a critical role in the etiology of inflammatory lung diseases. Nitric oxide (NO) has been suggested to play an antiinflammatory role through S-nitrosation of components of NF-B pathway. NO production can be modulated by changing the availability of its substrate, L-arginine. Arginases compete with NO synthases (NOSs) for their common substrate, L-arginine, and thereby have the potential to alter the signaling function of NO. The goal of the present study was to determine the impact of arginase manipulation on NO, and subsequent effects on NF-B activation, in lung epithelial cells. Our results demonstrate that reduction of arginase activity enhanced cellular content of NO and S-nitrosated proteins, and resulted in decreases in TNF-– or LPS-stimulated NF-B DNA binding and transcriptional activity, in association with enhanced S-nitrosation of p50. The effects of arginase inhibition on NF-B were reversed by the generic NOS inhibitor, N--nitro-L-arginine methyl ester (L-NAME), suggesting a causal role for NO in the attenuation of NF-B induced by arginase suppression. Conversely, overexpression of arginase I decreased cellular S-nitrosothiol content and enhanced IB kinase activity and NF-B DNA binding, and decreased S-nitrosation of p50. Collectively, our data point to a regulatory mechanism wherein NF-B is controlled through arginase-dependent regulation of NO levels, which may impact on chronic inflammatory diseases that are accompanied by NF-B activation and upregulation of arginases.

Key Words: arginase • lung epithelial cells • nitric oxide • NF-B • S-nitrosation

CLINICAL RELEVANCE Arginase was recently presented as a new player in asthma. This article suggests that arginase regulates transcription factor NF-B via NO-dependent redox changes. This would provide insights into the role of arginase in inflammatory disease.