title: High glucose concentrations induce TNF-α production through the down-regulation of CD33 in primary human monocytes.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departamento de Investigación en Microbiología, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Sección XVI, Ciudad de México, 14080, México.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gonzalez
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Herrera
authors.forename: Gloria
authors.initials: G
authors.lastname: Soldevila
authors.forename: Lourdes
authors.initials: L
authors.lastname: Garcia-Garcia
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Fabián
authors.forename: E Martha
authors.initials: EM
authors.lastname: Pérez-Armendariz
authors.forename: Karen
authors.initials: K
authors.lastname: Bobadilla
authors.forename: Silvia
authors.initials: S
authors.lastname: Guzmán-Beltrán
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sada
authors.forename: Martha
authors.initials: M
authors.lastname: Torres
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000975:Antioxidants; C571163:CD33 protein, human; D016207:Cytokines; D018836:Inflammation Mediators; C106644:SOCS3 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D024502:alpha-Tocopherol; D005947:Glucose