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Evidence for a Potent Antiinflammatory Effect of Rosiglitazone

Division of Endocrinology, Diabetes and Metabolism, State University of New York, and Kaleida Health, Buffalo, New York 14209

Address all correspondence and requests for reprints to: Paresh Dandona, M.D., Ph.D., Diabetes-Endocrinology Center of Western New York, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}kaleidahealth.org.

We have recently demonstrated a potent antiinflammatory effect of troglitazone, an agonist of peroxisome proliferator-activated receptor (PPAR) and a partial agonist of PPAR in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPAR agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor B (NFB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured.

Blood glucose concentration changed significantly at 6 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF- and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFB-binding activity and plasma MCP-1, CRP, SAA, and TNF- did not change in the obese and obese diabetic control groups.

We conclude that rosiglitazone, a selective PPAR agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.

This work was supported by Glaxo SmithKline and the McGowan Charitable Fund.

Abbreviations: BMI, Body mass index; CRP, C-reactive protein; ICAM-1, intercellular adhesion molecule-1; IB, inhibitor B; MCP-1, monocyte chemoattractant protein-1; MNC, mononuclear cell; NFB, nuclear factor B; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; sICAM-1, soluble ICAM-1.

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