Reduced stress tolerance of glutamine-deprived human monocytic cells is associated with selective down-regulation of Hsp70 by decreased mRNA stability

Abstract

In critically ill patients, clinicians observe a reverse correlation of survival and a decreased plasma concentration of the most abundant free amino acid, glutamine (Gln). However, in this context, the role of Gln remains largely elusive. Gln is used as an energy substrate by monocytes. Gln deprivation of these cells results in an increased susceptibility to cell stress and apoptosis, as well as in a reduced responsiveness to pro-inflammatory stimuli. We performed a systematic study to elucidate the molecular mechanism by which Gln depletion affects the heat stress response of the monocytic cell line U937. Proteomic analysis revealed that Gln depletion was associated with specific changes in the protein expression pattern. However, the overall level of tRNA-bound Gln remained unaffected. The stress protein heat shock protein (Hsp) 70 showed the highest reduction in protein synthesis. This was due to enhanced mRNA decay during Gln starvation while the transcriptional and the translational control of Hsp70 expression remained unchanged. A physiological Gln concentration and above was found to be necessary for maximum Hsp70 accumulation upon heat shock. Thus, the study shows a specific link between Gln metabolism and the regulation of heat shock proteins.

HSP-Mediated Cytoprotection of Mesothelial Cells in Experimental Acute Peritoneal Dialysis

“…Pharmacologic doses of glutamine increase binding affinity of heat shock factor-1 to its promoter, thereby increasing HSP transcription, as has similarly been shown for indomethacin and other NSAIDs (11). Furthermore, addition of glutamine stabilizes HSP-72 mRNA under stress conditions, which also results in increased HSP expression (10). In this study, glutamine supplementation of PDS during exposure caused a marked overexpression of HSP-27 and HSP-72 in mesothelial cells, and increased cell survival in the in vitro model of PD.…”

Glutamine's protection against sepsis and lung injury is dependent on heat shock protein 70 expression

“…Previous data have shown that GLN deficiency leads to an impaired ability to express HSP70 in both laboratory and clinical settings (1,6,16,22,24,29,31,33,36,44,48,54). Clinical critical illness is known to lead to significant GLN deficiency after 24 -72 h (10,15,25).…”

Understanding the mechanisms of glutamine action in critically ill patients

“…In summary, there is evidence that glutamine-starving cells show an increased susceptibility to cell stress and apoptosis, as well as a reduced responsiveness to pro-inflammatory stimuli (Fleshner et al 2004, Ropeleski et al 2005, Eliasen et al 2006. The maintenance of plasma glutamine levels is essential for cells energy status, as well as for their functions and inflammatory response.…”

“…Glutamine's beneficial effects on critical illnesses may result from enhanced heat shock proteins (HSP) expression (Singleton et al 2005b, Morrison et al 2006 expressed by leucocytes , monocytes (Eliasen et al 2006), and granulocytes (Ganter et al 2006). The heat shock proteins are a group of proteins essential to cellular survival under stressful conditions.…”

“…Glutamine starvation reduces the HSP70 expression since it decreases HSP70 mRNA expression (Eliasen et al 2006). As plasma glutamine depletion occurs during systemic inflammation, the impaired HSP70 expression under these conditions is likely to have deleterious effects on the survival and function of leucocytes, and may contribute to the immunosuppression observed in these patients.…”