Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor.

Abstract

Pancreatic islets contain cells that produce IL-18 and cells that express IL-18 receptors. In experimentally induced diabetes, islet failure correlates with IL-18 levels and diabetes is delayed with blockade of endogenous IL-18. We studied islet-derived IL-18 and responses to IL-18 in a mouse model of islet allograft transplantation. In vitro, IL-18-stimulated islets produced nitric oxide, which closely matched islet apoptosis. By neutralizing IL-18 activity with IL-18 binding protein (IL-18BP), we observed that islets produce bioactive IL-18. In vivo, transgenic mice overproducing IL-18BP (IL-18BP-Tg) exhibited delayed hyperglycemia induced by beta cell toxic streptozotocin. Similarly, cultured IL-18BP-Tg islets were protected from streptozotocin-induced apoptosis. In the transplant model, islets grafted from WT to IL-18BP-Tg mice achieved prolonged normoglycemia (P = 0.031). Improved graft function was also observed by using IL-18-deficient islets transplanted into WT recipients, demonstrating that endogenous, islet-derived IL-18 mediates IL-18-driven graft damage. Unexpectedly, islets from mice deficient in IL-18 receptor alpha chain (IL-18R) exhibited rapid graft failure (P = 0.024; IL-18- versus IL-18R-deficient grafts in WT recipients). In related studies, IL-18R-deficient splenocytes and macrophages produced 2- to 3-fold greater amounts of IL-18, TNFalpha, macrophage inflammatory protein 1, macrophage inflammatory protein 2, and IFNgamma upon stimulation with Con A, Toll-like receptor 2 agonist, or anti-CD3 antibodies. These data reveal a role for islet-derived IL-18 activity during inflammation-mediated islet injury. Importantly, discrepancies between IL-18- and IL-18R-deficient cells suggest that IL-18Ralpha chain is used by an inflammation-suppressing signal.

• Authors: Eli C Lewis, Charles A Dinarello
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 45 Pg. 16852-7 (Nov 07 2006) ISSN: 0027-8424 [Print] United States
• PMID: 17075045 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Intercellular Signaling Peptides and Proteins
• Interleukin-18
• Receptors, Interleukin-18
• interleukin-18 binding protein

Topics

• Animals
• Diabetes Mellitus, Experimental (immunology, metabolism, prevention & control)
• Female
• In Vitro Techniques
• Intercellular Signaling Peptides and Proteins (biosynthesis, genetics)
• Interleukin-18 (deficiency, pharmacology)
• Islets of Langerhans (drug effects, immunology, injuries, metabolism)
• Islets of Langerhans Transplantation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• Mice, Transgenic
• Receptors, Interleukin-18 (deficiency)
• Signal Transduction