Glutamine and interleukin-1[beta] interact at the level of Sp1 and nuclear factor-[kappa]B to regulate argininosuccinate synthetase gene expression

• Published in: The FEBS journal Vol. 274; no. 20; p. 5250
• Main Authors: Brasse-Lagnel, Carole, Lavoinne, Alain, Loeber, David, Fairand, Alain, Bôle-Feysot, Christine, Deniel, Nicolas, Husson, Annie
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.10.2007
• Subjects: Amino acids; Biochemistry; Cellular biology; Cytokines; Gene expression
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2007.06047.x

We previously demonstrated that the expression of the argininosuccinate synthetase (ASS) gene, a key step in nitric oxide production, is stimulated either by interleukin-1[beta][Brasse-Lagnel et al. (2005) Biochimie 87, 403-9] or by glutamine in Caco-2 cells [Brasse-Lagnel et al. (2003) J. Biol. Chem. 278, 52504-10], through the activation of transcription factors nuclear factor-[kappa]B and Sp1, respectively. In these cells, the fact that glutamine stimulated the expression of a gene induced by pro-inflammatory factors appeared paradoxical as the amino acid is known to exert anti-inflammatory properties in intestinal cells. We therefore investigated the effect of simultaneous addition of both glutamine and interleukin-1[beta] on ASS gene expression in Caco-2 cells. In the presence of both compounds for 4 h, the increases in ASS activity, protein amount and mRNA level were almost totally inhibited, implying a reciprocal inhibition between the amino acid and the cytokine. The inhibition was exerted at the level of the transcription factors Sp1 and nuclear-[kappa]B: (a) interleukin-1[beta] inhibited the glutamine-stimulated DNA-binding of Sp1, which might be related to a decrease of its glutamine-induced O-glycosylation, and (b) glutamine induced per se a decrease in the amount of nuclear p65 protein without affecting the stimulating effect of interleukin-1[beta] on nuclear factor-[kappa]B, which might be related to the metabolism of glutamine into glutamate. The present results constitute the first demonstration of a reciprocal inhibition between the effects of an amino acid and a cytokine on gene expression, and provide a molecular basis for the protective role of glutamine against inflammation in the intestine. [PUBLICATION ABSTRACT]