Abstract
Although both glucose deprivation and hypoxia have been reported to promote cascades of biological alterations that lead to induction of inflammatory mediators, we hypothesized that glucose deprivation and hypoxia might show neutral, synergistic or antagonistic effects to each other on gene expression of inflammatory mediators depending on the regulatory components in their promoters. Gene expression of interleukin 6 (IL-6) was analyzed by real-time PCR, ELISA, or Western blot. Effects of glucose deprivation and/or hypoxia on activation of signaling pathways were analyzed by time-dependent phosphorylation patterns of signaling molecules. We demonstrate that hypoxia antagonized the effects of glucose deprivation on induction of IL-6 gene expression in microglia, macrophages, and monocytes. Hypoxia also antagonized thapsigargin-induced IL-6 gene expression. Hypoxia enhanced phosphorylation of Akt, and inhibition of Akt was able to reverse the effects of hypoxia on IL-6 gene expression. However, inhibition of HIF-1/2α did not reverse the effects of hypoxia on IL-6 gene expression. In addition, phosphorylation of p38, but not JNK, was responsible for the effects of glucose deprivation on IL-6 gene expression.
Highlights
Glucose is the primary, if not the sole, energy substrate of the brain, and hypoglycemia in the brain causes a cerebral dysfunction ranging from mild behavioral impairment to coma [1]
The glucose deprivation-mediated interleukin 6 (IL-6) mRNA expression was not observed under the oxygen concentrations up to 7.5%; thereafter, it increased in an oxygen concentration dependent manner (Fig. 1C). These results suggest that oxygen depletion may have a counterbalancing effect on the glucose deprivation-induced expression of IL-6
Microglial activation, by itself, may not be beneficial or detrimental to ischemic insult, but the effect of microglia on cerebral ischemia may be dependent on the net balance of secreted molecules from microglia
Summary
If not the sole, energy substrate of the brain, and hypoglycemia in the brain causes a cerebral dysfunction ranging from mild behavioral impairment to coma [1]. Severe and prolonged hypoglycemia induces cell death in the brain, and studies demonstrated that mild hypoglycemia could cause changes in brain function even in the absence of neuronal death and prior to any detectable change in brain ATP concentrations [2,3]. Glucose deprivation disrupts calcium homeostasis in the endoplasmic reticulum (ER) and activates unfolded protein response [4,5,6], resulting in elevation of intracellular calcium concentration ([Ca2+]i) [7]. Thapsigargin, an inhibitor of sarco/ endoplasmic reticulum calcium ion ATPase, release calcium ion from the endoplasmic reticulum, raises [Ca2+]i, and activates ER stress [9]. A recent study demonstrated that glucose deprivation, but not hypoxia or amino acid deprivation, induced IL-6 gene expression in human renal cortical cells [12]
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