High glucose concentrations induce TNF-α production through the down-regulation of CD33 in primary human monocytes

CD33 expression was significantly decreased in monocytes from patients with type 2 diabetes, and higher levels of TNF-α, IL-8 and IL-12p70 were detected in the plasma of patients compared to healthy donors. Under high glucose conditions, CD33 protein and mRNA expression was significantly decreased, whereas spontaneous TNF-α secretion and SOCS-3 mRNA expression were increased in monocytes from healthy donors. Furthermore, the down-regulation of CD33 and increase in TNF-α production were prevented when monocytes were treated with the antioxidant α-tocopherol and cultured under high glucose conditions.Our results suggest that hyperglycemia down-regulates CD33 expression and triggers the spontaneous secretion of TNF-α by peripheral monocytes. This phenomenon involves the generation of ROS and the up-regulation of SOCS-3. These observations support the importance of blood glucose control for maintaining innate immune function and suggest the participation of CD33 in the inflammatory profile associated with type 2 diabetes.Both acute and chronic hyperglycemia are associated with inflammation [1]. Patients with newly diagnosed or established diabetes mellitus (DM) have significantly higher levels of acute-phase proteins and pro-inflammatory cytokines compared to control subjects without DM [2-5]. Monocytes isolated from patients with type 1 diabetes produce increased levels of IL-6, IL-1β and chemokines of the CXC family including IL-8 and interferon gamma-induced protein 10 (IP-10) [6]. Furthermore, monocytes from patients with DM produce higher levels of TNF-α and IL-8 in comparison to control monocytes [7-9].TNF-α production is thought to play a role in the generation of microvascular complications associated with diabetes, e.g., by enhancing chronic eye inflammation [10,11]. In addition to triggering acute and chronic inflammation, TNF-α regulates glucose and lipid metabolism and inhibits insulin production in pancreatic beta cells [12]. TNF-α is also produced in adipo