Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, Ciudad de México, 14080, México.
BMC Immunol. 2012 Apr 14;13:19. doi: 10.1186/1471-2172-13-19.
CD33 is a membrane receptor containing a lectin domain and a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) that is able to inhibit cytokine production. CD33 is expressed by monocytes, and reduced expression of CD33 correlates with augmented production of inflammatory cytokines, such as IL-1β, TNF-α, and IL-8. However, the role of CD33 in the inflammation associated with hyperglycemia and diabetes is unknown. Therefore, we studied CD33 expression and inflammatory cytokine secretion in freshly isolated monocytes from patients with type 2 diabetes. To evaluate the effects of hyperglycemia, monocytes from healthy donors were cultured with different glucose concentrations (15-50 mmol/l D-glucose), and CD33 expression and inflammatory cytokine production were assessed. The expression of suppressor of cytokine signaling protein-3 (SOCS-3) and the generation of reactive oxygen species (ROS) were also evaluated to address the cellular mechanisms involved in the down-regulation of CD33.
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.
CD33 是一种膜受体，包含凝集素结构域和细胞质免疫受体酪氨酸抑制基序（ITIM），能够抑制细胞因子的产生。CD33 表达于单核细胞，CD33 表达减少与促炎细胞因子如 IL-1β、TNF-α 和 IL-8 的产生增加相关。然而，CD33 在与高血糖和糖尿病相关的炎症中的作用尚不清楚。因此，我们研究了 2 型糖尿病患者新鲜分离的单核细胞中 CD33 的表达和炎性细胞因子的分泌。为了评估高血糖的影响，将健康供体的单核细胞在不同葡萄糖浓度（15-50mmol/L D-葡萄糖）下培养，并评估 CD33 表达和炎性细胞因子的产生。还评估了细胞因子信号转导抑制蛋白-3（SOCS-3）的表达和活性氧（ROS）的产生，以解决下调 CD33 所涉及的细胞机制。
2 型糖尿病患者的单核细胞中 CD33 的表达显著降低，且患者血浆中 TNF-α、IL-8 和 IL-12p70 的水平高于健康供体。在高葡萄糖条件下，健康供体单核细胞中 CD33 蛋白和 mRNA 表达显著降低，而自发性 TNF-α分泌和 SOCS-3 mRNA 表达增加。此外，当单核细胞用抗氧化剂 α-生育酚处理并在高葡萄糖条件下培养时，CD33 的下调和 TNF-α 产生的增加得到了预防。
我们的结果表明，高血糖下调 CD33 的表达并触发外周单核细胞自发性 TNF-α 的分泌。这种现象涉及 ROS 的产生和 SOCS-3 的上调。这些观察结果支持控制血糖对维持先天免疫功能的重要性，并表明 CD33 参与与 2 型糖尿病相关的炎症特征。
