Glucose regulates expression of pro-inflammatory genes IL-1β and IL-12 through a mechanism involving hexosamine biosynthesis pathway dependent regulation of α-E catenin in the RAW 264.7 macrophage cell line

Dissanayake, Waruni C.; Oh, Jin Kyo; Sorrenson, Brie; Shepherd, Peter R.

High glucose levels are associated with changes in macrophage polarization and evidence indicates that the sustained or even short-term high glucose levels modulate inflammatory responses in macrophages. However, the mechanism by which macrophages can sens e the changes in glucose levels are not clearly understood. We find that high glucose levels rapidly increase the α-E catenin protein level in RAW264.7 macrophages. We also find an attenuation of glucose induced increase of α-E catenin when hexosamine biosynthesis pathway is inhibited either with glutamine depletion or with the drugs azaserine and tunicamycin. This indicates the involvement of hexosamine biosynthesis pathway in this process. Then, we investigated the potential role of α-E catenin in glucose induced macrophage polarization. We find that the reduction of α-E catenin level using siRNA attenuates the glucose induced change of IL-1β mRNA level under LPS stimulated condition. Further, we identified that the depletion of α-E catenin also decreases the IL-12 gene expression in basal glucose conditions leading to a reduction of glucose induced changes in IL-12. Together this indicates that α-E catenin can sense the changes in glucose levels in macrophages via hexosamine biosynthesis pathway and also can modulate the glucose induced gene expression of inflammatory markers such as IL-1-β and IL-12. This identifies a new part of the mechanism by which macrophages are able to respond to changes in glucose levels.