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¹ Hannover Medical School, Institute of Clinical Biochemistry, 30625 Hannover, Germany² Department of Cell Biology and Genetics, University of Maringá, 87020-900 Maringá, Brazil

(Correspondence should be addressed to E Gurgul-Convey; Email: Gurgul-Convey.Ewa{at}mh_hannover.de)

(Present address of K L A Souza is the Department of Physiology and Biophysics, University of Campinas, Brazil)

^* (K L A Souza and E Gurgul-Convey equally contributed to this work)

Pro-inflammatory cytokines cause β-cell dysfunction and death. The aim of this study was to investigate the interactions between different pro- and anti-inflammatory cytokines and their effects on apoptotic β-cell death pathways. Insulin-producing RINm5F cells were exposed to different combinations of cytokines. Gene expression analyses of manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS) were performed by real-time RT-PCR. Cell viability was measured by the MTT assay, NFB activation using a SEAP reporter gene assay, protein expression by western blotting and caspase-3 activity using the DEVD cleavage method. IL-1β, tumour necrosis factor (TNF) and a combination of all three pro-inflammatory cytokines increased while IFN alone did not affect NFB activity and iNOS gene and protein expression. Interestingly, the anti-inflammatory cytokines IL-4, IL-13 and IL-10 decreased IL-1β-stimulated NFB activation and iNOS expression. IL-1β, TNF and the pro-inflammatory cytokine combination also increased MnSOD gene and protein expression. But IL-4, IL-13 and IL-10 did not affect MnSOD expression and did not modulate IL-1β-stimulated MnSOD expression. Caspase-3 activity was increased by IL-1β and the pro-inflammatory cytokine combination, and to a lesser extent by TNF. In contrast, IFN had no effect on caspase-3 activity. IL-4, IL-13 and IL-10 decreased caspase-3 activity and increased viability of insulin-producing cells treated with pro-inflammatory cytokines. The anti-inflammatory cytokines counteracted the cytotoxic effects of pro-inflammatory cytokines in insulin-producing cells. This was achieved through the reduction of nitrosative stress. Thus, a balance between the anti-inflammatory and the pro-inflammatory cytokines is of crucial importance for the prevention of pancreatic β-cell destruction.