Immune Netw.  2012 Jun;12(3):113-117. 10.4110/in.2012.12.3.113.

Apoptosis of Human Islet Cells by Cytokines

• Kim S
• Kim KA
• Suk K
• Kim YH
• Oh SH
• Lee MK
• Kim KW
• Lee MS

• KMID: 2168009
• DOI: http://doi.org/10.4110/in.2012.12.3.113

Abstract

FasL, perforin, TNFalpha, IL-1 and NO have been considered as effector molecule(s) leading to beta-cell death in autoimmune diabetes. However, the real culprit(s) of beta-cell destruction have long been elusive despite intense investigation. Previously we have suggested IFNgamma/TNFalpha synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFNgamma and TNFalpha but neither cytokine alone, induced classical caspase-dependent apoptosis in murine insulinoma and pancreatic islet cells. IFNgamma treatment conferred susceptibility to TNFalpha-induced apoptosis on otherwise resistant murine insulinoma cells by STAT1 activation followed by IRF-1 induction. Here we report that IFNgamma/TNFalpha synergism induces apoptosis of human pancreatic islet cells. We also observed STAT1 activation followed by IRF-1 induction by IFNgamma treatment in human islet cells. Taken together, we suggest that IFNgamma/TNFalpha synergism could be involved in human islet cell death in type 1 diabetes, similar to murine type 1 diabetes.

Keyword

Diabetes; Apoptosis; Autoimmunity; Cytokines; Inflammatory mediators

MeSH Terms

Animals
Apoptosis
Autoimmunity
Cytokines
Diabetes Mellitus, Type 1
Humans
Insulinoma
Interleukin-1
Islets of Langerhans
Mice
Mice, Inbred NOD
Perforin
Tumor Necrosis Factor-alpha
Cytokines
Interleukin-1
Perforin
Tumor Necrosis Factor-alpha

Figure

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  Figure 1 Human islet cell death by IFNγ/TNFα synergism. Single human islet cells were incubated with the cytokine combination for 5 days before assay. A combination of IFNγ (1,000 U/ml) and TNFα (10 ng/ml), but neither cytokine alone, induced human islet cell death as measured by MTT assays. IL-1β (17.5 ng/ml) had negligible effects. Graphs from one representative experiment among three independent experiments are shown. Values represent the means±SD from triplicate experiments. The means were compared using Student's unpaired t test. **p<0.01; ns, not significant (A). Apoptosis of human islet cells induced by IFNγ/TNFα. Nuclear condensation demonstrated by Hoechst staining (upper) or electron microscopy (lower) revealed that human islet cell death by IFNγ/TNFα was a classical apoptosis (B). IFNγ activates STAT1 and induces IRF-1 expression in human islet cells. Western blot analyses demonstrated that treatment of human islet cells with IFNγ (1,000 U/ml) for 30 min induced STAT1 phosphorylation (C). IFNγ also induced IRF-1 expression after 48 h of treatment (D).

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