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B and AP-1 Activation in Islets and Prevents Diabetes Induced with Streptozotocin in Mice
2
* German Diabetes Center, German Diabetes Research Institute at the Heinrich-Heine-University of Düsseldorf, D-40223 Düsseldorf, Germany; Institute of Pathology, Heinrich-Heine-University of Düsseldorf, D-40225, Düsseldorf, Germany; Institute of Pathophysiology, University of Catania, I-95131 Catania, Italy; and Wyeth Research, Andover, Massachusetts 01810
To whom requests for reprints should be addressed at 1 Deutsches Diabetes-Forschungsinstitut, Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany. E-mail: gleich{at}ddfi.uni-duesseldorf.de
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)-
and interferon (IFN)-
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)-ß1 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)-
B and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-) of NF-B inhibitor (IB). Furthermore, the effect of recombinant human (rh)IL-11 on MLD-STZ diabetes, insulitis, cytokines, IKK-, NF-B, and AP-1 was analyzed in islets.
Interleukin-11 prevented diabetes without affecting insulitis; attenuated TNF- and IFN- response; and stimulated IL-4 production and inhibited activation of IKK-, NF-B, 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-B and AP-1 might play a key role.
Key Words: MLD-STZ diabetes • cytokines • NF-B • AP-1 • IKK-
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