Interleukin-11 inhibits NF-kappaB and AP-1 activation in islets and prevents diabetes induced with streptozotocin in mice.
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)-alpha and interferon (IFN)-gamma 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)-kappaB and activator protein (AP)-1, which are involved in gene activation of proinflammatory cytokines, and on the cytosolic kinase (IKK-alpha) of NF-kappaB inhibitor (IkappaB). Furthermore, the effect of recombinant human (rh)IL-11 on MLD-STZ diabetes, insulitis, cytokines, IKK-alpha, NF-kappaB, and AP-1 was analyzed in islets. Interleukin-11 prevented diabetes without affecting insulitis; attenuated TNF-alpha and IFN-gamma response; and stimulated IL-4 production and inhibited activation of IKK-alpha, NF-kappaB, 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-kappaB and AP-1 might play a key role.
Lgssiar
Abdelhakim
A
German Diabetes Center, German Diabetes Research Institute at the Heinrich-Heine-University of Düsseldorf, D-40223 Düsseldorf, Germany.
Hassan
Mohamed
M
Schott-Ohly
Patricia
P
Friesen
Nadira
N
Nicoletti
Ferdinando
F
Trepicchio
William L
WL
Gleichmann
Helga
H
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D051550:I-kappa B Kinase; D017370:Interleukin-11 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*
D017931:DNA Primers; D017370:Interleukin-11; D016328:NF-kappa B; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D013311:Streptozocin; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse