High mobility group box 1 contributes to wound healing induced by inhibition of dipeptidylpeptidase 4 in cultured keratinocytes

Abstract

Dipeptidyl peptidase 4 (DPP4) is expressed in various tissues, including the skin, and DPP4 inhibitors, that are currently used for the treatment of diabetes, may be effective also for complications of diabetes that affect the skin. To assess the role of DPP4 in keratinocytes, after creating a scratch wound in a monolayer of NTCC 2544 cells, we evaluated DPP4 expression and monitored wound repair over time, after treatment with the DPP4 inhibitor 1(((1-(hydroxymethyl)cyclopentyl)amino)acetyl)2,5-cis-pyrrolidinedicarbonitrile (DPP4-In). Expression of DPP4 increased early and was maintained up to 48 h following the scratch as shown by western blot and immunostaining. Treatment with 10 μM DPP4-In reduced DPP4 expression and significantly accelerated wound repair. This effect did not involve enhanced cell proliferation as shown by MTT proliferation assay, the lack of changes of cell cycle profiles and the slight inhibition of ERK phosphorylation. Enhancement of wound repair by DPP4 inhibition was prevented by the non-specific MMPs inhibitor GM6100 (5 μM). Treatment with DPP4-In increased the expression of high mobility group box 1 (HMGB1), a substrate of this enzyme, and exposure of NCTC 2544 cells to DPP4-In and exogenous HMGB1 (10 nM) produced a non-additive effect. Finally the healing promoting effect of DPP4-In was prevented by pretreatment with a neutralizing anti-HMGB1 antibody. The present results suggest that DPP4 inhibition contributes to enhanced wound healing by inducing keratinocytes to migrate into a scratched area. This effect seems to be independent of cell proliferation and involves enhanced production of HMGB1.

Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population‐based, cohort study in Taiwan

“…The pathophysiological mechanisms of the relationship between DPP‐4 inhibitors and development BP remain unclear. DPP‐4, also known as CD26, is a 110‐kD transmembrane protein and expressed on the cell membrane surface, including endothelial cells, bronchial epithelial cells, keratinocytes and immune cells . DPP‐4 is a multifunctional protein, such as a proteolytic enzyme, receptor and costimulatory protein, and exerts its physiological roles in processes of nutrition, cell adhesion and immune response .…”

“…DPP-4, also known as CD26, is a 110-kD transmembrane protein and expressed on the cell membrane surface, including endothelial cells, bronchial epithelial cells, keratinocytes and immune cells. 20,21 DPP-4 is a multifunctional protein, such as a proteolytic enzyme, receptor and costimulatory protein, and exerts its physiological roles in processes of nutrition, cell adhesion and immune response. 22,23 In an animal model, DPP-4 inhibition promotes eosinophil activation in the skin by enhancing the activity of pro-inflammatory chemokines.…”

MiR-153 regulates metastases of gastric cancer through Snail

“…Scratch wound healing assay was performed as has been described previously [14]. Cells were seeded in 24-well plates at a density of 10 4 cells/well in complete Dulbecco's modified Eagle's medium (DMEM) and cultured to confluence.…”

Involvement of DPP IV/CD26 in cutaneous wound healing process in mice

“…Major sources of DPP IV/CD26 in the skin are epidermal keratinocytes and dermal fibroblasts . Results from in vitro studies indicated that DPP IV/CD26 inhibition increases the ability of keratinocytes to repair thorough the high‐mobility group protein 1 (HMGB1), one of DPP IV/CD26 substrates involved in cell migration and wound healing . Moreover, it has been suggested that a well‐known DPP IV/CD26 substrate, glucagon‐like peptide‐1 (GLP‐1), may promote the up‐regulation of hypoxia‐inducible factor 1α (HIF‐1α), a transcriptional factor playing crucial role in angiogenesis and improve the production of multiple angiogenic growth factors including vascular endothelial growth factor (VEGF) .…”