Effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS-induced colitis

Abstract

Background: We investigated the effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B (NF-kappaB) and signal transducers and activators of transcription (STAT) in a rat model of experimental colitis.

Methods: Colitis was induced in male Wistar rats by intracolonic administration of 30 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Glutamine (25 mg/kg) was given by rectal route daily for 7 days.

Results: Glutamine significantly reduced gross damage and histopathological scores and prevented the decrease of anal pressure and the elevated myeloperoxidase activity observed in the colon of animals receiving TNBS. TNBS administration induced a marked increase of vascular cell adhesion molecule (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) protein levels. These inflammatory events were associated with increased protein level of NF-kappaB p50 and p65 subunits in the nucleus and significant phosphorylation/degradation of the inhibitor IkappaBalpha. Protein levels of the phosphorylated forms of STAT1, STAT5, and Akt were elevated in animals with colonic damage. All these effects were inhibited by administration of glutamine. Increases in the cytosolic concentration of TBARS and hydroperoxide-initiated chemiluminescence, markers of oxidative stress, and levels of tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) were significantly inhibited at 48 hours of TNBS instillation in glutamine-treated animals.

Conclusions: Inhibition of the expression of proinflammatory mediators that are regulated by the NF-kappaB and STAT signaling pathways contribute to the therapeutical effect of glutamine in the TNBS model of experimental colitis. These effects may be brought about by inhibition of oxidative stress and reduced expression of proinflammatory cytokines.