High-Glucose Environment Inhibits p38MAPK Signaling and Reduces Human β-3 Expression in Keratinocytes

Abstract

Diabetes mellitus is characterized by elevated plasma glucose and increased rates of skin infections. Altered immune responses have been suggested to contribute to this prevalent complication, which involves microbial invasion. In this study we explored the effects of a high-glucose environment on the innate immunity of keratinocytes by focusing on β defensin-3 (BD3) using in vivo and in vitro models. Our results demonstrated that the perilesional skins of diabetic rats failed to show enhanced BD3 expression after wounding. In addition, high-glucose treatment reduced human BD3 (hBD3) expression of cultured human keratinocytes. This pathogenic process involved inhibition of p38MAPK signaling, an event that resulted from increased formation of advanced glycation end products. On the other hand, toll-like receptor-2 expression and function of cultured keratinocytes were not significantly affected by high-glucose treatment. In summary, high-glucose conditions inhibited the BD3 expression of epidermal keratinocytes, which in turn contributed to the frequent occurrences of infection associated with diabetic wounding.

High-Glucose Environment Enhanced Oxidative Stress and Increased Interleukin-8 Secretion From Keratinocytes

“…These results corroborated with a previous study showing that EGFR-ERK cascade regulates the production of IL-8 in lung cancer cells (24). It should be noted that our experimental condition did not significantly alter the physiologic status (viability, growth, and differentiation) of culture keratinocytes as demonstrated in our previous study (21). …”

“…1 C ) It has been reported that nuclear factor-κB (NF-κB), p38 MAPK, and ERK are involved in IL-8 secretion of keratinocytes (22,23). Since we had previously demonstrated that upregulation of NF-κB and p38 MAPK was not observed in high glucose–cultivated keratinocytes (21), we focused on ERK signaling. As demonstrated in Fig.…”

Antimicrobial Peptides: Their History, Evolution, and Functional Promiscuity

“…HBD3 is highly expressed in keratinocytes, especially at wound sites in response to the growth factors such as EGF, transforming growth factor-α, and insulin growth factor-1 [310][311][312], and it has been shown that the peptide promotes the proliferation and migration of keratinocytes through phosphorylation of the EGF receptor and STAT proteins [289]. However, this study also showed that when the skin of diabetic rats was wounded, RBD3 induction was negligible and similar observations were made for HBD3 expression in human keratinocytes under various glucose-treatment conditions, indicating that both defensins were dysfunctional under hyperglycemic conditions [313]. However, this study also showed that when the skin of diabetic rats was wounded, RBD3 induction was negligible and similar observations were made for HBD3 expression in human keratinocytes under various glucose-treatment conditions, indicating that both defensins were dysfunctional under hyperglycemic conditions [313].…”

A Novel Lipopeptide from Skin Commensal Activates TLR2/CD36-p38 MAPK Signaling to Increase Antibacterial Defense against Bacterial Infection

“…Specifically, p38 MAPK has been shown to play an important role in hBD2 and hBD3 production in epithelial cells such as keratinocytes [16], [17]. We thus hypothesized that p38 MAPK might be the downstream molecule of TLR2 involved in the induction of hBDs by LP01.…”