Limited availability of l-arginine increases DNA-binding activity of NF-κB and contributes to regulation of iNOS expression

Abstract

The impact of nutrients on gene expression can be mediated by the availability of amino acids. The aim of this study is to examine the effect of limited availability of L: -arginine on the DNA-binding activity of NF-kappaB, a dominant transcription factor in inflammation, and the consequence for the expression pattern of inducible nitric oxide synthase (iNOS) in murine keratinocytes. Low availability of L: -arginine leads to activation and increased DNA-binding activity of NF-kappaB and induction of iNOS messenger RNA (mRNA) in the absence of cytokines, but not to translation into iNOS protein. Cytokine challenge at low L: -arginine also enhances iNOS mRNA expression, but translation into iNOS protein is diminished, leading to lowered nitric oxide production. The decrease in iNOS protein expression is mediated by the phosphorylation of the translation initiation factor eIF2alpha subunit, a key regulator of cellular translation. In contrast, the mRNA expression of the NF-kappaB-dependent genes IL-1alpha and cationic amino acid transporter-2 (CAT-2) are not affected by the availability of L-arginine. These results demonstrate that the availability of L: -arginine can play a role in the control of gene expression by augmenting the DNA-binding activity of NF-kappaB, which can affect the initiation and progression of dermal inflammation.