High-glucose environment reduces human ß-defensin-2 expression in human keratinocytes: implications for poor diabetic wound healing.

ABSTRACT

BACKGROUND: Wound healing is a dynamic and complicated process in which inflammation, re-epithelialization and angiogenesis play important roles. Intriguingly, all three processes have been found to be defective during diabetic wound healing conditions. One common denominator associated with regulation of these events is human ß-defensin-2 (hBD2). It has been shown that skin wounding induces cutaneous hBD2 expression, and diabetic wounds have been associated with inadequate hBD expression. OBJECTIVES: The current study was launched to explore the effects of a high-glucose environment on cultured human keratinocytes. METHODS: Human keratinocytes were exposed to indicated culture conditions. The mRNA and protein levels of hBD2 were determined, and activation of relevant pathways was evaluated. The small interference RNA approach was used to validate the functional role of the proposed pathway on hBD2 expression. RESULTS: We showed that high-glucose cultivated keratinocytes expressed reduced levels of hBD2 and phosphorylated signal transducer and activator of transcription (pSTAT)-1 constitutively. In addition, pSTAT-1 signalling is critically involved in hBD2 expression. Formation of advanced glycation endproducts, a direct consequence of a high-glucose environment, involves constitutive downregulation of pSTAT-1 and hBD2. The addition of interleukin-1ß, an important cytokine during the cutaneous wound healing process, enabled the upregulation of hBD2 expression of both normal- and high-glucose cultivated keratinocytes, but the absolute levels of hBD2 were still significantly lower in the high-glucose-treated group. CONCLUSIONS: As hBD2 plays multifaceted roles during the wound healing process, the inadequate expression of hBD2 during diabetic conditions contributes to impaired wound healing.