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

This Article Abstract Full Text (PDF) Supplemental Data All Versions of this Article: 279/40/41271    most recent C400360200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohara-Imaizumi, M. Articles by Nagamatsu, S. Search for Related Content PubMed PubMed Citation Articles by Ohara-Imaizumi, M. Articles by Nagamatsu, S. Social Bookmarking                      What's this?

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

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

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Accumulating evidence over the past 30 years suggests that -cells are destroyed by an autoimmune process in type 1 diabetes mellitus (T1D)¹ (1). The prediabetic period in humans is characterized by the presence of islet cell autoantibodies (2), which seem to have a close correlation with histological evidence of autoimmunity (3). There are already subtle changes in -cell function during this period, including both disproportionately elevated proinsulin/insulin levels (4, 5) and a preferential loss of the first phase insulin secretion in response to an intravenous glucose challenge (6–9). Of note, -cell suppression precedes -cell death in T1D, as suggested by results obtained in islets isolated from prediabetic non-obese diabetic mice (10, 11) or from a patient who died immediately after diagnosis of T1D (12). This initial -cell functional suppression might be due to exposure to cytokines. Indeed, our previous observations (13) indicate that islet exposure to cytokines under in vitro conditions reproduce the disproportionately elevated proinsulin/insulin levels observed in prediabetic patients. Moreover, microarray analysis of purified -cells or insulin-producing INS-1 cells cultured in the presence of IL-1 or IL-1 + IFN- showed inhibition of the expression of several genes involved in the exocytosis of insulin granules, including SNAP-25, VAMP-2, and Rab3 (14, 15). This raised the intriguing possibility that cytokines could also contribute for the defective first phase insulin release observed in prediabetic patients.

The biphasic kinetics of insulin release is probably explained by the presence of a small population of docked granules, released during the first phase of insulin secretion, and the subsequent arrival of "newcomer" granules targeted to the plasma membrane and released during the second phase of insulin secretion (16, 17). The three SNAREs (N-ethylmaleimide-sensitive fusion protein attachment protein receptors), namely SNAP-25, syntaxin 1, and synaptobrevin (VAMP) are expressed in pancreatic -cells and play a crucial role for granule fusion with the cell membrane (18–20). To better understand the mechanisms involved in insulin granule exocytosis, we have recently developed an approach based on a green fluorescence protein (GFP)-tagged insulin granule system, combined with total internal reflection microscopy (TIRFM) (21). This system allows us to observe the motions of single insulin granules during approach, docking, and fusion with the membrane and also to localize endogenous t-SNAREs such as SNAP-25 and syntaxin-1 in the cell membrane (22, 23). We have presently utilized this system to characterize insulin granule motion in -cells treated for 24 h with cytokines. The data obtained suggest that IL-1 reduces the docking/fusion of insulin granules in pancreatic -cells, preferentially decreasing the first phase of exocytosis, along with a decrease in SNAP-25 mRNA expression and SNAP-25 clusters on the plasma membrane.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
Islet Cell Preparation, Adenovirus Infection, and Exposure to Cytokines—Pancreatic islets of Langerhans were isolated from male Wistar rats by collagenase digestion, as described (17). Isolated islets were dispersed in calcium-free Krebs-Ringer buffer (KRB) containing 1 mM EGTA and cultured on fibronectin-coated (Koken Co. Ltd., Tokyo, Japan) high refractive index glass (Olympus, Tokyo, Japan) in RPMI 1640 medium (Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen), 200 units/ml penicillin, and 200 µg/ml streptomycin at 37 °C in an atmosphere of 5% CO₂. For labeling the insulin secretory granules, pancreatic -cells were infected with recombinant adenovirus Adex1CA insulin-GFP as described previously (17). Two days after infection, they were exposed for 24 h to IL-1 (100 units/ml; kindly provided by Dr. C. W. Reynolds, NCI, Bethesda, MD) and/or IFN- (2000 units/ml; Invitrogen, Baesley, Scotland). For determination of mRNA expression (see below) and insulin content, rat pancreatic -cells were purified by autofluorescence-activated cell sorting, cultured overnight, and exposed for 24 h to IL-1 and/or IFN-, and insulin was measured by radioimmunoassay as described previously (14, 24).

Immunohistochemical Analysis—Single cells cultured on high refractive index glass with and/or without cytokines were fixed, made permeable with 2% paraformaldehyde, 0.1% Triton X-100, and processed for immunohistochemistry as described previously (22). They were labeled with monoclonal anti-insulin antibody (Sigma) and anti-SNAP-25 antibody (Wako, Co. Ltd., Osaka, Japan) and then processed with goat anti-mouse IgG conjugated to Alexa Fluor-488 (Molecular Probes, Eugene, OR). Immunofluorescence was detected with TIRFM. This procedure allowed us to evaluate the number of docked insulin granules and SNAP-25 clusters.

TIRF Microscopy for Observing the Immunofluorescence and for Monitoring GFP-tagged Insulin Granule Motion—The Olympus total internal reflection system was used with minor modifications as described previously (21). Briefly, light from an argon laser (488 nm) was introduced to an inverted microscope (IX70, Olympus) through a single-mode fiber and two illumination lenses; the light was focused at the back focal plane of a high aperture objective lens (Apo 100xOHR; NA 1.65, Olympus). To observe the fluorescence image of Alexa Fluor-488, we used a 488-nm laser line and a long pass 515-nm filter. To monitor the motion of the single insulin granules, the adenovirus-infected and cytokine-treated cells on the glass coverslip (Olympus) were mounted in an open chamber and incubated for 30 min at 37 °C in KRB containing 110 mM NaCl, 4.4 mM KCl, 1.45 mM KH₂PO₄, 1.2 mM MgSO₄, 2.3 mM calcium gluconate, 4.8 mM NaHCO₃, 2.2 mM glucose, 10 mM HEPES (pH 7.4), and 0.3% bovine serum albumin. Cells were then transferred to the thermostat-controlled stage (37 °C), and stimulation with glucose was achieved by addition of 52 mM glucose-KRB into the chamber (final concentration: 22 mM glucose). For observation of GFP, we used a 488-nm laser line for excitation and a 515-nm long pass filter for the barrier. Diodomethane sulfur immersion oil was used to make contact between the objective lens and the coverslip, and the measured penetration depth was about 45 nm.

Acquiring the Images and Analysis—Images were collected by a cooled charge-coupled device camera (Micromax, MMX-512-BFT, Princeton Instruments; operated with Metamorph 4.6, Universal Imaging, Downingtown, PA). Images were acquired every 300 ms. The analyses, including tracking (the single projection of different images) and area calculations were performed using Metamorph software. To analyze the data, fusion events were manually selected, and the average fluorescence intensity of individual granules in a 1 x 1-µm square placed over the granule center was calculated. The number of fusion events was manually counted while looping about 30,000 frame time lapses. Sequences were exported as single TIFF files and further processed using Adobe Photoshop 6.0, or they were converted into Quick Time movies (see supplemental material). This procedure allowed us to dynamically evaluate single insulin granule motion.

mRNA Isolation and RT-PCR—mRNA isolation and RT-PCR were performed as described previously (25). The number of cycles was selected to allow linear amplification of the cDNA under study. For semiquantitative PCR, the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as control. We have previously shown (26) and confirmed in the present experiments that a 6–24-h exposure to IL-1 and IFN- do not affect GAPDH mRNA expression in purified -cells. Thus, GAPDH expression was as follows after, respectively, 6 and 24 h treatments (optical density values; means ± S.E. of four experiments): 6 h, control, 8.6 ± 0.5; IL-1, 8.4 ± 0.8; IFN-, 8.5 ± 0.4; IL-1 + IFN-, 8.2 ± 0.9; 24 h, control, 6.2 ± 0.6; IL-1, 7.1 ± 0.8; IFN-, 6.1 ± 0.8; IL-1 + IFN-, 6.7 ± 1.2. The primer sequences were as follows: GAPDH, 5' TCC CTC AAG ATT GTC AGC AA 3' (forward) and 5' AGA TCC ACA ACG GAT ACA TT 3' (reverse); SNAP-25, 5' GAT GTC GGC ATC AGG ACT TT 3' (forward) and 5' GAG TCA GCC TTC TCC ATG AT 3' (reverse); and VAMP-2, 5' TCA GCA CTT AAG TCC CTG AG 3' (forward) and 5' CGT AGA CGA TAC GTT ATC GG 3' (reverse).

Statistical Analysis—Data are presented as means ± S.E., and comparison between groups was performed by t test or by Wilcoxon Rank Sum Test or by analysis of variance followed by Fisher's test and regression analysis.

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 
IL-1, but Not IFN-, Reduced the Number of Insulin Granules Docked to the Plasma Membrane—To examine the docking status of insulin granules by cytokines exposure, rat primary pancreatic -cells were exposed to IL-1 or IFN- for 24 h, immunostained with anti-insulin antibody, and then examined by TIRF microscopy. TIRF imaging depicts the single insulin granules docked to the plasma membrane, enabling accurate docked insulin granule counting (17). We defined "docked granule" when the vesicle was located within 100 nm of the plasma membrane as reported somewhere (27). As shown in Fig. 1, the number of docked insulin granules in -cells treated with IL-1 was markedly decreased (248.9 ± 35.1 per 200 µm² in control versus 92.6 ± 31.0 in IL-1; n = 11 cells; p < 0.0001), but there was no difference between IFN--treated (240.6 ± 59.1 per 200 µm²) and control cells. We have shown previously that a 24-h exposure of -cells to IL-1 does not affect insulin content and cell viability (24, 28, 29), and in experiments performed in parallel with the determinations of mRNA expression (see below), we observed that a 24-h exposure to IL-1 + IFN- also failed to affect -cell insulin content: control -cells, 28 ± 9 ng of insulin/10⁶ cells; IL-1 + IFN-, 25 ± 5 ng of insulin/10⁶ cells (n = 4). Thus, the decreased number of docked insulin granules in IL-1-treated -cells is not due to a decrease in insulin content but is probably caused by IL-1-mediated impairment of insulin granule docking.

View larger version (72K): [in this window] [in a new window]   FIG. 1. Histochemical study of insulin granules docked to the plasma membrane. The upper panel shows the typical TIRF images of docked insulin granules in control, IL-1, or IFN--treated -cells. Pancreatic -cells were prepared from Wistar rats, exposed to IL-1 or IFN- for 24 h, and then immunostained for insulin. The lower panel shows the number of insulin granules morphologically docked to the plasma membrane. Individual fluorescent spots shown in TIRF images were manually counted per 200 µm2; n = 11 cells. *, p < 0.0001 versus control.

View larger version (62K): [in this window] [in a new window]   FIG. 2. TIRF images and the quantitative analysis of SNAP-25 clusters on the -cell plasma membrane. Pancreatic -cells were treated as described the legend of Fig. 1 and immunostained for SNAP-25. The upper panel shows the typical TIRF images of SNAP-25 clusters on the plasma membrane. The lower panel shows the number of SNAP-25 clusters per 200 µm2 counted using TIRF images; n = 14 cells. *, p < 0.0001 versus control.

View larger version (26K): [in this window] [in a new window]   FIG. 3. RT-PCR analysis of SNAP-25 (A) and VAMP-2 (B) mRNA expression. Rat -cells (105 cells/condition) were exposed for 6 or 24 h to control condition, IL-1 (50 units/ml), IFN- (1000 units/ml)), or IL-1 + IFN-. After these time points, the cells were harvested, mRNA extracted, and the RT-PCR performed with the equivalent of 1.5 x 103 cells. PCR band intensities were expressed as optical density corrected for GAPDH expression. The data are presented as percentage of the respective controls, which received an arbitrary value 1 in each experiment; n = 4 experiments. *, p < 0.01 versus control group.

View larger version (63K): [in this window] [in a new window]   FIG. 4. TIRF images and analysis of single GFP-labeled insulin granule motion. After normal rat pancreatic -cells were prepared and cultured as described under "Experimental Procedures," they were infected with Adex1CA insulin-GFP. Two days later, infected cells were exposed to IL-1 and IFN- for 24 h. On the experimental day, cells were preincubated with KRB, 2.2 mM glucose for 30 min and then transferred to the thermostat-controlled stage and stimulated with 22 mM glucose. The real-time motion of GFP-labeled insulin granules was imaged close to the plasma membrane (300-ms intervals) (see movies: S1 (control), S2 (IL-1-treated), S3 (IFN--treated cells)). The represented pictures next to the histogram are images before stimulation. The graph shows the histogram of the number of fusion events (per 200 µm2) at 60-s intervals after stimulation. The black column shows the fusion from previously docked granules (resident), while the open column indicates that from newcomers.

	FOOTNOTES

 
^* 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.

¹ The abbreviations used are: T1D, type 1 diabetes mellitus; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; IL, interleukin; IFN, interferon; KRB, Krebs-Ringer buffer; RT, reverse transcriptase; SNAP-25, synaptosmal-associated protein of 25 kDa; VAMP, vesicle-associated membrane protein; SNARE, soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor; TIRF, total internal reflection fluorescence; TIRFM, TIRF microscopy.

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TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

 

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This Article Abstract Full Text (PDF) Supplemental Data All Versions of this Article: 279/40/41271    most recent C400360200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohara-Imaizumi, M. Articles by Nagamatsu, S. Search for Related Content PubMed PubMed Citation Articles by Ohara-Imaizumi, M. Articles by Nagamatsu, S. Social Bookmarking                      What's this?