Altered gene expression profiles associated with enhanced skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate in streptozotocin-diabetic mice

To examine the mechanisms of diabetes-enhanced inflammation, ear inflammation was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in streptozotocin (STZ)-injected diabetic and control mice. The inflammatory response was determined from ear thickness and histology. The mRNA expression of several inflammation-related genes 8, 24 and 32h after TPA treatment was determined by quantitative real-time RT-PCR. Ear thickness did not differ between the two groups at 8h, but was greater in the diabetic mice than control mice at 24 and 32h (late phase). STZ-diabetic conditions variously affected TPA-induced gene expression. The changes 8h after TPA treatment probably reflected transcriptional regulation, and the genes were divided into three groups, up-regulated (IL-6, MCP-1, HO-1 and SOCS3), unregulated (IL-1beta, TNF-alpha and IL-10) and down-regulated (RANTES) genes. TPA-induced gene expression of cytokines, except for RANTES, peaked at 8h and significantly declined in the late phase in control mice, while the expression of IL-1beta and TNF-alpha did not decline in the late phase in the diabetic mice. This result indicated the destabilization process for these mRNA, a type of post-transcriptional regulation, to be impaired under STZ-induced diabetic conditions; however, TPA-induced gene and protein expression of TTP, an RNA-binding protein involved in mRNA decay, were adversely enhanced in the diabetic mice. These findings suggested that STZ-induced diabetes affected the transcriptional and post-transcriptional control of TPA-induced inflammation, and greater mRNA levels of IL-1beta and TNF-alpha in the late phase were probably responsible for the diabetes-enhanced inflammation. ► We produced a simple diabetes-enhanced inflammation model in mice. ► Diabetes variously modified cytokine mRNA expression at inflamed sites. ► Diabetes suppressed the reduction in mRNA levels of TNF-alpha and IL-1beta. ► TTP was not directly involved in the mRNA stabilization of TNF-alpha and IL-1beta.