Prevention of autoimmune diabetes in NOD mice by troglitazone is associated with modulation of ICAM-1 expression on pancreatic islet cells and IFN-γ expression in splenic T cells

• Published in: Biochemical and biophysical research communications Vol. 304; no. 2; pp. 378 - 384
• Main Authors: Augstein, Petra, Dunger, Annemarie, Heinke, Peter, Wachlin, Gerhild, Berg, Sabine, Hehmke, Bernd, Salzsieder, Eckhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.05.2003
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Chromans - pharmacology; Chromans - therapeutic use; Cytokine expression; Cytokines - biosynthesis; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - prevention & control; Female; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; ICAM-1; Intercellular Adhesion Molecule-1 - metabolism; Interferon-gamma - biosynthesis; Interleukin-1 - pharmacology; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Mice; Mice, Inbred NOD; NOD mice; Pancreatic islet cells; Rats; Spleen - cytology; Spleen - immunology; Splenocytes; T-Lymphocytes - immunology; Thiazoles - pharmacology; Thiazoles - therapeutic use; Thiazolidinediones; Troglitazone; Type-1 diabetes; Splenocytes; Cytokine expression; ICAM-1; Pancreatic islet cells; NOD mice; Troglitazone; Type-1 diabetes
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(03)00590-4

Thiazolidinediones acting as PPAR-γ agonists are a new generation of oral antidiabetics addressing insulin resistance as a main feature of type-2 diabetes. In accordance to our results, pre-clinical studies have demonstrated that the thiazolinedione troglitazone prevents the development of insulin-dependent autoimmune type-1 diabetes. To investigate whether TGZ acts by affecting the ICAM-1/LFA-1 pathway and/or the Th1/Th2 cytokine balance in NOD mice, we analysed the IL-1β-induced ICAM-1 expression on islet-cells and the LFA-1, CD25, IL-2, IFN-γ, IL-4, and IL-10 expression on splenocytes. After 200 days of oral TGZ administration, islet cells from TGZ-treated NOD mice showed a reduced ICAM-1 expression in response to the pro-inflammatory cytokine IL-1β. The expression of the ligand LFA-1 on CD4 + and CD8 + T-cells was comparable to that of placebo- and untreated controls. Also, the expression of Th1/Th2 cytokines was comparable in groups receiving TGZ or Placebo. Nevertheless, the investigated NOD mice segregated into IFN-γ low- and IFN-γ high producers as revealed by cluster analysis. Interestingly, the majority of TGZ-treated mice belonged to the cluster of IFN-γ low producers. Thus, the prevention of autoimmune diabetes in NOD mice by TGZ seems to be associated with suppression of IL-1β-induced ICAM-1 expression leading to a reduced vulnerability of pancreatic β-cells during the effector stage of β-cell destruction. In addition, IFN-γ production was modulated, implicating that alteration of the Th1/Th2 cytokine balance might have contributed to diabetes prevention. The findings of this study suggest that TGZ exerts its effects by influencing both the β-cells as the target of autoimmune β-cell destruction and the T-cells as major effectors of the autoimmune process.