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.
Heat shock response provides cells with higher tolerance against a variety of insults such as heavy metals, reperfusion injury, and endotoxin. In addition, heat treatment is known to affect ion transport mechanisms associated with vital cellular processes, including cell volume regulation. However, there has been no reports to date of a heat shock effect on cellular volume regulation itself. The aim of our study was to investigate whether the heat shock response influences volume regulation of cells. Human promonocytic U937 cells display an increase in volume in response to osmotic shrinkage. This regulatory volume increase (RVI) is mediated mainly by ion antiporters. U937 cells exposed to a temperature of 45 degrees C for 10 min (heat shock) show an enhancement of RVI after hypertonic challenge compared with untreated cells. Also, heat-treated cells display a lower intracellular pH (pHi) than untreated cells; similar control mechanisms are believed to be involved in regulating both pHi and RVI. In agreement with this, heat-shocked cells demonstrated increased activity of an HCO3(-)-independent/DIDS-sensitive pHi down-regulator, postulated to be a Cl-/HCO3- exchange. We suggest that heat shock-mediated RVI enhancement is at least partially mediated by an increased Cl-/HCO3- exchange. Our results indicate that heat shock of U937 cells activates a hitherto unknown cytoprotective effect that may help cells to overcome hypertonic challenge.
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