Glutamine attenuates inflammation and NF-kappaB activation via Cullin-1 deneddylation.
Glutamine (GLN) can inhibit NF-kBeta activation and cytokine expression following sepsis. NF-kappaB activation and inflammatory cytokine expression, depend on neddylation of Cullin-1 (Cul-1) to proceed. Our aim was to evaluate whether GLN inhibits Cul-1 neddylation, and further determine if GLN-mediated Cul-1 deneddylation attenuates NF-kappaB activation and subsequent cytokine expression following experimental sepsis in the mouse. Sepsis-induced via cecal ligation and puncture (CLP) led to a significant increase in lung Cul-1 neddylation. GLN administration post-sepsis led to enhanced lung Cul-1 deneddylation and attenuated NEDD8 expression (p<0.01 vs. saline). Cul-1 deneddylation was associated with decreased NF-kappaB activation and IkappaB alpha degradation in GLN treated mice (( *)p<0.01 vs. saline). Lastly, GLN treatment led to a significant decrease in lung TNF-alpha and IL-6 post-sepsis. These are the first data describing a direct effect of GLN on Cul-1 deneddylation and provide a possible mechanistic explanation for GLN's anti-inflammatory effects.
Singleton
Kristen D
KD
Department of Anesthesiology, University of Colorado Health Sciences Center, Leprino Office Building (LOB), 12401 East 17th Avenue, B113, Aurora, CO 80045, USA.
Wischmeyer
Paul E
PE
D000818:Animals; D044842:Cullin Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism*
C100318:Cullin 1; D044842:Cullin Proteins; D016207:Cytokines; D016328:NF-kappa B; D005973:Glutamine