Interleukin-11 Inhibits N-κB and AP-1 Activation in Islets and Prevents Diabetes Induced with Streptozotocin in Mice

Abstract

This laboratory has reported that multiple low doses of streptozotocin (MLD-STZ) similarly upregulate the T helper (Th)1-type proinflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ in islets of both the diabetes-susceptible male and the diabetes-resistant female C57BL/6 mice and that MLD-STZ downregulates the anti-inflammatory Th2-type cytokines interleukin (IL)-4 and IL-10, as well as the anti-inflammatory Th3-type cytokine-transforming growth factor (TGF)β1 in islets of male, but not female, mice. Thus, diabetes is associated with a relative preponderance of local proinflammatory cytokines. Here, we investigated the effects of MLD-STZ on the anti-inflammatory cytokine IL-11 and the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-α) of NF-κB inhibitor (IκB). Furthermore, the effect of recombinant human (rh)IL-11 on MLD-STZ diabetes, insulitis, cytokines, IKK-α, NF-κB, and AP-1 was analyzed in islets.

Interleukin-11 prevented diabetes without affecting insulitis; attenuated TNF-α and IFN-γ response; and stimulated IL-4 production and inhibited activation of IKK-α, NF-κB, and AP-1. The results demonstrated the potential of rhIL-11 in preventing MLD-STZ diabetes through enhancement of anti-inflammatory responses in islets. In this process, the transcription factors NF-κB and AP-1 might play a key role.