Blocking Type I Interferon Signaling Rescues Lymphocytes from Oxidative Stress, Exhaustion, and Apoptosis in a Streptozotocin-Induced Mouse Model of Type I Diabetes

Hany M Ibrahim,Danny M Rabah,Badr Mohamed Badr,Gamal Badr,Heba M Saad Eldien,Ibrahim A El-Elaimy

doi:10.1155/2013/148725

Hany M Ibrahim, Danny M Rabah + Show 4 more

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https://doi.org/10.1155/2013/148725

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Abstract

Elevated levels of type I interferon (IFN) during type 1 diabetes mellitus (T1D) are associated with a defective immune response. In the present study, we investigated whether blocking type I IFN signaling during streptozotocin- (STZ-) induced T1D in mice improves lymphocyte proliferation and escape from continuous apoptosis. Three groups of mice were examined: diabetic mice, type I IFN signaling-incompetent diabetic mice, and control nondiabetic mice. We first found that diabetes induction was accompanied by an elevation in the plasma levels of reactive oxygen species (ROS), hydroperoxide, malondialdehyde (MDN), and the proinflammatory cytokines IL-1α, IL-1β, IL-6, and CXCL10. Blocking type 1 IFN signaling in diabetic mice significantly decreased the levels of oxidative stress and proinflammatory cytokines. In addition, lymphocytes from diabetic mice exhibited a marked reduction in their proliferative capacity, increased apoptosis, upregulation of the exhaustion marker PD-1, and aberrant phosphorylation of STAT1, STAT2, AKT and IκB-α. Interestingly, following the blocking of type I IFN signaling in diabetic mice, the lymphocytes exhibited restored proliferative capacity, decreased apoptosis, normal expression of PD-1, and normal phosphorylation of STAT1, STAT2, AKT and IκB-α. Our data suggest that elevated levels of type I IFN during T1D trigger lymphocyte exhaustion and a defective lymphocyte-medicated immune response.

Highlights

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the specific destruction of pancreatic β cells, which produce insulin [1]
In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the β cells, is used to trigger the initial β-cell death leading to diabetes induction [10]
We found that the percentage of β cells that underwent apoptosis was 68% in STZ-treated mouse versus 8% in control mice (Figure 1(c))

Summary

Introduction

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the specific destruction of pancreatic β cells, which produce insulin [1]. Extensive studies have focused on the role of the immune system in the development of T1D, from the initiation of disease to eventual beta-cell destruction [2, 3]. As both free-radical production and antioxidant defenses may be disturbed in diabetes [4], it has been suggested that oxidative stress may be partly responsible for the development of diabetic complications [5]. Consistent with this, oxidative stress has been implicated in the pathogenesis of insulin-dependent diabetes mellitus in several studies [6,7,8].

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