Glutamine inhibits cytokine-induced apoptosis in human colonic epithelial cells via the pyrimidine pathway

Evans, Mary; Jones, Dean P.; Ziegler, Thomas R.

doi:10.1152/ajpgi.00072.2005

Cited by 51 publications

(38 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since glutamine is able to inhibit TNF-␣ production by interference with the NF-B signaling pathway (14,54), the effect of glutamine on apoptosis could be explained by the observed reduced production of TNF-␣. However, in Caco-2 cells glutamine inhibits death receptor ligandinduced apoptosis by modulating pyrimidine synthesis (15). In the present study we are unable to evaluate which of these proposed mechanisms is crucial for the observed reduced TNF-␣ production and apoptotic response but could reason that by reduction of TNF-␣ and apoptosis in the epithelial layer glutamine is able to reduce disease activity in GvHD.…”

Section: Discussionmentioning

confidence: 60%

Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model

Noth

Häsler

Stüber

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Although a profound barrier dysfunction has been reported, little is known about the pathophysiological mechanism evoking gastrointestinal graft-vs.-host disease (GI-GvHD) and apparent therapeutic options. The aim of this study was to evaluate the influence of oral glutamine on the course of GI-GvHD in an acute semiallogenic graft-vs.-host disease (GvHD) in irradiated B6D2F1 mice. An acute semiallogenic GvHD was induced by intraperitoneal injection of lymphocytes from C57BL/6 mice to irradiated B6D2F1 mice. Half of the GvHD animals received oral glutamine supplementation for 6 days started at the time of lymphocyte transfer. Six days after induction of the semiallogenic GvHD, jejunum specimens were prepared. The expression of the proinflammatory cytokine TNF-α and the tight junction protein occludin was investigated by PCR. Histological changes along with the apoptotic response were evaluated and intestinal permeability was assessed. Animals with GvHD showed a strong increase in paracellular permeability as a sign of the disturbed barrier function. TNF-α expression was significantly increased and the expression of the tight junction protein occludin decreased. GvHD led to mucosal atrophy, crypt hyperplasia, crypt apoptosis, and a disintegration of the tight junctions. Glutamine-treated mice showed reduced expression of TNF-α, increased occludin expression, fewer histological changes in the jejunum, smaller number of apoptotic cells in the crypt, and reduced gastrointestinal permeability. In conclusion, oral glutamine seems to have beneficial effects on the severity of inflammatory changes in the course of GvHD and might be a therapeutic option.

show abstract

Section: Discussionmentioning

confidence: 60%

Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model

Noth

Häsler

Stüber

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…One study of note by Evans et al indicated that glutamine can prevent intestinal cell apoptosis via the pyrimidine pathway [32]. This provides an interesting mechanistic explanation for glutamine's benefi ts.…”

Section: Discussionmentioning

confidence: 99%

“…A number of in-vitro studies [32,33] have examined the role of glutamine in preventing apoptosis following stress or injury. One study of note by Evans et al indicated that glutamine can prevent intestinal cell apoptosis via the pyrimidine pathway [32].…”

Section: Discussionmentioning

confidence: 99%

Glutamine decreases intestinal nuclear factor kappa B activity and pro-inflammatory cytokine expression after traumatic brain injury in rats

Chen

Shi

et al. 2008

Inflamm. res.

View full text Add to dashboard Cite

show abstract

“…GS inhibition did not reduce cell cycles but selectively affected cell numbers, similar to inhibiting pyrimidine synthesis. GS was previously shown to selectively support pyrimidine and not purine synthesis, and pyrimidine rather than purine synthesis was required to protect cells from inflammation-induced apoptosis (31,32). Inflammation and tissue injury are physiological conditions of Gln reduction, and GS is de-repressed under low Gln, nucleotide starvation, and by glucocorticoid hormones (22,(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Restricting Glutamine or Glutamine-Dependent Purine and Pyrimidine Syntheses Promotes Human T Cells with High FOXP3 Expression and Regulatory Properties

Metzler

Gfeller

Guinet

2016

The Journal of Immunology

View full text Add to dashboard Cite

T cell subsets differ in their metabolic requirements, and further insight into such differences might be harnessed to selectively promote regulatory T cells (Tregs) for therapies in autoimmunity and transplantation. We found that Gln restriction during human T cell activation favored CD4 T cells with high expression of the Treg transcription factor FOXP3. This resulted from shrinking numbers and reduced proliferation of activated FOXP3lo/−CD4 T cells while FOXP3hiCD4 T cell numbers increased. This gain was abolished by blocking Gln synthetase, an enzyme that responds to Gln and purine/pyrimidine deficiencies. The shift toward FOXP3hiCD4 T cells under Gln restriction was recapitulated with inhibitors of Gln-dependent pyrimidine and purine syntheses that together closely mimicked declining cell numbers and cell cycles, and by small interfering RNA knockdown of the respective rate-limiting Gln-consuming enzymes CAD and PPAT. FOXP3hi-enriched CD25hiCD4 T cells from these cultures inhibited proliferation, but they also produced effector cytokines, including IL-17A. The latter was largely confined to CTLA-4hi-expressing FOXP3hi-enriched CD25hiCD4 T cells that suppressed proliferation more weakly than did CTLA-4lo/−CD25hiFOXP3hi–enriched T cells. A causal link between high IL-17A production and impaired suppression of proliferation could not be demonstrated, however. Collectively, these results reveal a Gln synthetase–dependent increase and resilience of FOXP3hi cells under Gln restriction, and they demonstrate that impaired Gln-dependent nucleotide synthesis promotes FOXP3hi cells with regulator properties. It remains to be investigated to what extent the concomitant retention of IL-17A–producing CD4 T cells may limit the therapeutic potential of Tregs enriched through targeting these pathways in vivo.

show abstract

Glutamine inhibits cytokine-induced apoptosis in human colonic epithelial cells via the pyrimidine pathway

Abstract: tamine inhibits cytokine-induced apoptosis in human colonic epithelial cells via the pyrimidine pathway.

Cited by 51 publications

References 43 publications

Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model

Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model

Glutamine decreases intestinal nuclear factor kappa B activity and pro-inflammatory cytokine expression after traumatic brain injury in rats

Restricting Glutamine or Glutamine-Dependent Purine and Pyrimidine Syntheses Promotes Human T Cells with High FOXP3 Expression and Regulatory Properties

Contact Info

Product

Resources

About