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J. Biol. Chem., Vol. 279, Issue 40, 41271-41274, October 1, 2004

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The Cytokine Interleukin-1 Reduces the Docking and Fusion of Insulin Granules in Pancreatic -Cells, Preferentially Decreasing the First Phase of Exocytosis^*

Mica Ohara-Imaizumi, Alessandra K. Cardozo¶, Toshiteru Kikuta, Decio L. Eizirik, and Shinya Nagamatsu||

From the Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan and the Laboratory of Experimental Medicine, Free University Brussels (ULB), 808 Route de Lennik, CP 618 B-1070 Brussels, Belgium

The prediabetic period in type I diabetes mellitus is characterized by the loss of first phase insulin release. This might be due to islet infiltration mediated by mononuclear cells and local release of cytokines, but the mechanisms involved are unknown. To determine the role of cytokines in insulin exocytosis, we have presently utilized total internal reflection fluorescence microscopy (TIRFM) to image and analyze the dynamic motion of single insulin secretory granules near the plasma membrane in live -cells exposed for 24 h to interleukin (IL)-1 or interferon (IFN)-. Immunohistochemistry observed via TIRFM showed that the number of docked insulin granules was decreased by 60% in -cells treated with IL-1, while it was not affected by exposure to IFN-. This effect of IL-1 was paralleled by a 50% reduction in the mRNA and the number of clusters of SNAP-25 in the plasma membrane. TIRF images of single insulin granule motion during a 15-min stimulation by 22 mM glucose in IL-1-treated -cells showed a marked reduction in the fusion events from previously docked granules during the first phase insulin release. Fusion from newcomers, however, was well preserved during the second phase of insulin release of IL-1-treated -cells. The present observations indicate that IL-1, but not IFN-, has a preferential inhibitory effect on the first phase of glucose-induced insulin release, mostly via an action on previously docked granules. This suggests that -cell exposure to immune mediators during the course of insulitis might be responsible for the loss of first phase insulin release.

Received for publication, August 2, 2004 , and in revised form, August 13, 2004.

^* This work was supported by Grants-in-aid for Scientific Research (C) 14570130 (MO-I) and (B) 15390108 (SN) and Scientific Research on Priority Areas 16044240 (MO-I) from the Japan Ministry of Education, Culture, Sports, Sciences, and Technology and by grants from the European Foundation for the Study of Diabetes (EFSD)/Novo Nordisk Diabetes Research Fund, Action de Recherche Concertees (ARC) de la Communaute Francaise, Belgium, and the Fonds National de la Recherche Scientifique (FNRS), Belgium. This work has been conducted in collaboration with and partially supported by the Juvenile Diabetes Research Foundation (JDRF) Center for Prevention of -Cell Destruction in Europe under Grant 4-2002-457. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Quick Time movies S1–S3.

^¶ Recipient of a Postdoctoral Fellowship from the JDRF.

^|| To whom correspondence should be addressed. Tel.: 81-422-47-5511 (ext. 3437); Fax: 81-422-47-5538; E-mail: shinya{at}kyorin-u.ac.jp.

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