Exp Clin Endocrinol Diabetes 2006; 114(10): 555-562
DOI: 10.1055/s-2006-948306
Article

© J. A. Barth Verlag in Georg Thieme Verlag KG · Stuttgart · New York

Osteopontin Deficiency Impacts the Pancreatic Th1/Th2 Cytokine Profile Following Multiple Low Dose Streptozotocin-Induced Diabetes

H. A. Arafat 1 , E. Lada 1 , A. K. Katakam 1 , N. Amin 1
  • 1Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA
Further Information

Publication History

Received: May 8, 2006 First decision: May 19, 2006

Accepted: June 21, 2006

Publication Date:
19 December 2006 (online)

Abstract

Osteopontin (OPN) is a phosphorylated acidic glycoprotein that causes chemotaxis of macrophages and downregulation of nitric oxide synthesis. OPN has been shown to be involved in the pathogenesis of autoimmune diseases. Here, we tested the hypothesis that increased expression of pancreatic OPN in experimental diabetes has a protective role. The immune response phenotype associated with the induction of diabetes was evaluated in male OPN knockout (KO) and wild type (WT) mice. Multiple low dose streptozotocin (STZ) (MLDS), 40 mg/kg, was injected intraperitoneally for 5 days to establish a model for autoimmune diabetes. Glucose levels and body weight were evaluated in the vehicle and STZ treated groups. ELISA assay was used to monitor OPN serum levels in the WT diabetic mice. Histological studies evaluated insulitis development and Western blot analysis was employed to evaluate the expression levels of Th1 cytokines (TNF-α and IFN-γ) and Th2 cytokines (IL-10 and IL-4). Immunohistochemistry was employed to localize IL-4 in the diabetic WT pancreata. Both WT and KO mice developed diabetes. In the WT, OPN serum levels were significantly upregulated 1 day after STZ injection. Pancreatic islets appeared larger in the KO group. Mild lymphocytic infiltrate and apoptosis were detected in the WT diabetic islets, while no signs of inflammation were detected in the KO group. WT diabetics showed upregulation of both Th1 and Th2 cytokines, whereas in the diabetic KO a mild upregulation of Th1 cytokines was detected with significant downregulation of IL-4. In the diabetic WT mice, IL-4 was localized in the interlobular connective tissue. Our studies show that the pancreatic immune response to MLDS diabetes is balanced between the Th1 and Th2 in the WT animals. KO mice show mild polarization towards the Th1 response. Although OPN is a known promoter for Th1 responses, it appears to have a regulatory control over the Th2 response in MLDS.

References

Correspondence

Hwyda Arafat, M.D., Ph.D.·Assistant Professor 

Departments of Surgery Pathology, Anatomy, and Cell Biology

Thomas Jefferson University

1015 Walnut Street

Suite 618 Curtis

Philadelphia

PA 19107

Phone: 215-955-6383

Fax: 215-955-2878

Email: hwyda.arafat@jefferson.edu