Elizabeth Holmes
Biology 1615
Saturday Lab
Cutting Edge: IL-4-Mediated Protection of Primary B
Lymphocytes from Apoptosis Via Stat6-Dependent
Regulation of Glycolytic Metabolism
IL-4 is a pleiotropic cytokine that acts on and prevents the death of naïve B lymphocytes which require extrinsic signals to maintain viability and promote growth.
Through the up-regulation of antiapoptotic proteins Bcl-2 family proteins function in part to maintain the mitochondrial membranes integrity. In apoptosis and glucose metabolism the role of mitochondria suggests these two cellular processes can be coupled. Even though studies implicating glucose utilization in growth factor-dependent survival of hemopoietic cells. IL-4 is not proven to maintain B cells viability of the glucose energy metabolism. Although a growing body of evidence supports the belief that impaired gluycolysis may limit the oxidizable substrates availability that maintains the mitochondrial membranes potential, in which will trigger apoptosis. The binding o IL-4 to its receptor activates several signal transduction cascades which serve as docking sites for Stat6. These cells undergo apoptosis in the presence of IL-4, which has been linked to impaired Bcl-xl induction. This chain recruits insulin receptor substrate-2, allowing association with the regulatory subunit. IL-4 helps survival through the recruitment of
IRS-2 and P13K activation. Despite the presence of IL-4 the B cells deficient in IRS-2 or p85 will still undergo apoptosis. These cellular targets remain to be identified in B cells, but studies suggest that hemopoietic cells signal modulates glucose metabolism.
This article demonstrates that IL-4-increases glucose transport and glycolsis in B cells. If IL-4 is blocked the glycolytic flux will lead to the decreased survival of the B

cell. The activity of IRS-2 and p13K are dispensable for IL-4-induced glycoliysis, but in
B cell the glycolysis is dependent upon Stat6. The first findings indicate an essential role for glucose energy metabolism in the pro-survival activity of IL-4 implicating Stat6 signals the regulation of glucose utilization. The data points to a critical role for glycoltic metabolism in maintaining primary B cell viability and raise the question as to why increased glucose uptake and glycolytic metabolism is required for the survival pathway driven by IL-4. They believe one possibility is in the absence of IL-4, B cells can’t import or use glucose to maintain normal housekeeping functions. It was found by restricting glycolytic metabolism it results in the failure to maintain cellular homeostasis, which will eventually trigger apoptosis.
The results differed from reports demonstrating a role for P13k activity in the survival of T cells and IL-3-dependent hemopoietic cell lines, and this discrepancy may show that inherent differences in the pro-survival signaling pathways used by B cells and these other types of cells. Because of this unknown functions of Stat6-dependent signaling in regulating glucose energy metabolism have been identified. Currently the molecular basis underlying Stat6-dependent up-regulation of gluycolyic flux is unknown.
Stat6 might control the transcriptional activation of genes encoding glycolytic enzymes in response to IL-4. This is supported by recent gene expressions pro-filing studies that revealed increased levels of transcripts encoding several glycolytic enzymes following
IL-4 treatment of B cells. IL-4-medicated Strat6 signaling might regulate glucose energy metabolism with phosphorylation; the rat-limiting glycolytic enzymes. The conclusion of the article indicated additional studies would be needed to delineate the regulatory functions of Stat6 in glycolytic homeostasi