High-mobility group box 1 enhances the inflammatory process in diabetic lung

Diabetes mellitus generates metabolic changes associated with inflammatory events that may eventually affect all body tissues. Both high-mobility group box 1 (HMGB1) and beta-catenin are active players in inflammation. The study aimed to determine whether HMGB1 modulates the beta-catenin activity in supporting inflammation, using an experimental type 1 diabetes mouse model. The protein and gene expression of HMGB1 were significantly increased (2-fold) in the diabetic lung compared to control and were positively correlated with the HMGB1 levels detected in serum. Co-immunoprecipitation of HMGB1 with RAGE co-exists with activation of PI3K/AKT1 and NF-kB signaling pathways. At the same time beta-catenin was increased in nuclear fraction (3.5 fold) while it was down-regulated in diabetic plasma membrane (2-fold). There was no difference of beta-catenin gene expression between the control and diabetic mice. beta-Catenin phosphorylation at Ser552 was higher in diabetic nuclear fraction, suggesting that AKT1 activation promotes beta-catenin nuclear translocation. In addition, c-Jun directly binds beta-catenin indicating the transcriptional activity of beta-catenin in diabetes, sustained by significantly COX2 increase by 6-fold in the cytosolic extract of diabetic lung compared to control. Taken together, the data support the new concept that HMGB1 maintains the inflammation through RAGE/AKT1/beta-catenin pathway in the diabetic lung. (C) 2015 Elsevier Inc. All rights reserved.