1 Division of Nutritional Sciences and 2 Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801
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ABSTRACT |
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To better clarify
individual roles of interferon (IFN)- and IFN-
in
-cell
pathology during the onset of type 1 diabetes mellitus, we compared the
effects of these cytokines on insulin production and major
histocompatibility complex (MHC) gene expression in pancreatic
-cell
lines. IFN-
but not IFN-
decreased secreted and intracellular
insulin concentrations in
TC6-F7 and
TC3 cells. Likewise, IFN-
but not IFN-
treatment of
-cells upregulated mRNA expression of
MHC class IA antigen-processing
genes and surface expression of class
IA molecules. Alternatively, class
IA MHC expression was upregulated
by IFN-
and IFN-
in the
P388D1 macrophage cell line. The
observation of constitutive Ifn-
6
mRNA expression by a differentiated
-cell line substantiates
previous indications that local expression of IFN-
in islets may
trigger insulitis. Evidence that IFN-
, a product of infiltrating
leukocytes, directly decreases
-cell glucose sensitivity and
increases MHC class IA cell
surface expression supports the postulate that IFN-
magnifies the
insulitic process.
type I diabetes; major histocompatibility complex class IA locus; insulitis
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INTRODUCTION |
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TYPE ONE DIABETES IS AN autoimmune disease
characterized by the selective destruction of pancreatic
-cells by autoreactive T lymphocytes (1, 4, 36). The cytokines
interferon (IFN)-
and IFN-
have been associated with type 1 diabetes pathogenesis both in humans and in animal models of autoimmune
diabetes (3, 17, 33). For example, pancreatic
Ifn-
mRNA expression and the
presence of immunoreactive IFN-
in
-cells of patients with recent-onset type 1 diabetes have been reported (12, 17, 37). In
addition, IFN-
expression has been associated with hyperexpression of major histocompatibility complex (MHC) class
IA antigens in human islets (12,
37). In two rodent models of autoimmune diabetes, the diabetes-prone
DP-BB rat and streptozotocin-treated mice,
Ifn-
mRNA expression in islets
precedes insulitis and diabetes (16). Also, transgenic mice harboring a
hybrid human insulin promoter-Ifn-
construct develop hypoinsulinemic diabetes accompanied by insulitis
(39). Those studies indicate a potential role for IFN-
in the
pathogenesis of autoimmune diabetes but do not demonstrate mechanisms
by which IFN-
contributes to
-cell demise.
Pancreatic expression of IFN- in animal models of autoimmune
diabetes has also been reported (31, 35). Transgenic mice harboring the
Ifn-
gene linked to the human
insulin promoter develop insulitis and subsequently autoimmune diabetes
(34). Alternatively, administration of anti-IFN-
antibody decreases diabetes incidence in the BB/Wor rat and in nonobese diabetic mice (9,
24). We have demonstrated that IFN-
concurrently decreases insulin
production and upregulates cell surface expression of class
IA MHC molecules on pancreatic
-cell lines, mimicking two major alterations of the prediabetic
-cell (2). To better clarify individual roles of IFN-
and IFN-
in
-cell pathology, the present study compares the effects of these
cytokines on glucose responsiveness, the mRNA expression of
Ifn-
6, the expression of class
IA MHC antigen-processing and
antigen presentation genes, and cell surface expression of class
IA MHC molecules in the pancreatic
TC3 and
TC6-F7 cell lines.
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MATERIALS AND METHODS |
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Cells.
TC3 and
TC6-F7 cells were established from
-cell
adenomas derived from transgenic mice harboring a hybrid rat insulin
promoter-simian virus 40 large T-antigen gene construct (10, 14, 20).
The more differentiated
TC6-F7 cells were derived by soft agar
cloning and maintain normal glucose sensitivity (20). The
P388D1 murine macrophage cell line
was obtained from the American Type Culture Collection (ATCC;
Rockville, MD; ATTC TIB-63). Cells were serially passaged in
75-cm2 tissue culture flasks
(Corning Glass, Corning, NY) and maintained in DMEM supplemented with a
final glucose concentration of 25 mM and with Eagle's minimum
essential medium nonessential amino acid supplement (GIBCO, Grand
Island, NY), 44 mM sodium bicarbonate, 15 mM HEPES, 10,000 U/ml
penicillin plus 10,000 µg/ml streptomycin, 15% (vol/vol) horse serum
(HS), and 2.5% (vol/vol) fetal clone II (FC; HyClone, Logan, UT). HS
was heat inactivated at 56°C for 30 min. Cultures were maintained
in a humidified atmosphere of 95% air and 5%
CO2 at 37°C.
Cell culture studies.
To characterize the individual effects of IFN- and IFN-
on
intracellular insulin content and secretion in response to glucose,
TC6-F7 cells were seeded at a density of 2 × 105 cells/well into 24-well tissue
culture plates (Corning). On reaching 70-90% confluence, culture
medium was replaced with fresh DMEM supplemented with 5% FC without
glucose for 24 h to minimize basal levels of insulin secretion.
Cultures were then exposed for 3 days to treatment medium consisting of
DMEM with 15% HS, 2.5% FC, and 25 mM glucose, without or with
increasing doses of recombinant mouse IFN-
(6, 12, 25, and 50 U/ml;
Genentech, South San Francisco, CA; sp act 9.8 × 106 U/ml) or recombinant human
IFN-
-A/D (50, 100, and 200 U/ml; Hoffmann-La Roche, Nutley, NJ; sp
act 1.4 × 108
U/ml). This recombinant IFN-
, a hybrid of human IFN-A and IFN-D proteins (A/D Bgl II), is biologically
active on mouse cells (32, 39). After cytokine exposure, cultures were
washed three times in DMEM without glucose. Cells were then
preincubated in DMEM (0 mM glucose) for 1 h and subjected to an insulin
secretion test for 2 h in DMEM supplemented with glucose (25 mM) and
5% FC.
-Cell-conditioned medium and acid-ethanol culture extracts
(1.5% HCl in 70% ethanol; overnight at 4°C) were collected at the
end of the 2-h secretion tests and stored at
20°C until
assayed for insulin.
Insulin RIA and cellular protein determinations. Insulin concentrations in cell-conditioned medium and acid-ethanol cell extracts were determined by double-antibody RIA as described previously (22). Rat insulin was used as a standard. Standards, antibodies, and 125I-labeled insulin were obtained from Linco Research (St. Louis, MO). Inter- and intra-assay coefficients of variation were 9% and 3%, respectively. Cells were harvested and sonicated in 0.5 ml of PBS plus 0.1% Triton X-100 (Fisher Biotech, Fair Lawn, NJ) for later protein determination by the Bradford microassay method (Bio-Rad, Richmond, CA). Insulin concentrations are expressed as microunits per microgram of soluble cellular protein. Statistical analysis of treatment differences was made by paired t-tests and P values <0.05 were considered significant.
Cellular DNA content.
To evaluate the individual effects of IFN- and IFN-
on cell
viability, total cellular DNA concentrations were measured from
TC6-F7 cultures treated with cytokines as described above for insulin production studies. Cells were then harvested and sonicated in
0.5 ml of DNA assay buffer (50 mM
Na2HPO4,
2 M NaCl, and 2 mM EDTA, pH 7.4). Total DNA concentrations from crude
homogenates were determined by fluorometry using bisbenzimide (Hoechst
33258; Molecular Probes, Eugene, OR) as described previously (21).
Northern blot and RT-PCR analyses.
TC6-F7 cells and P388D1
macrophages were grown in 75-cm2
tissue culture flasks (Corning) in DMEM (25 mM glucose) supplemented with 15% HS plus 2.5% FC. On reaching ~70% confluence, cultures were exposed to fresh DMEM without or with IFN-
(100 U/ml) or IFN-
(50 U/ml) for 3 days. After exposure to IFN-
or IFN-
, total cellular RNA was isolated by a single-step guanidinium
thiocyanate method (7). One microgram of total RNA for each sample was reverse transcribed with avian myeloblastosis virus RT using an oligo(dT) primer. Sequence-specific primers were designed on the basis
of respective mouse cDNA nucleotide sequences (GenBank, Bethesda, MD)
to amplify specific regions of
Ifn-
6, class
IA MHC antigen-processing and
antigen presentation genes, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNAs. Reverse transcription reactions and PCR
amplification were carried out in a thermal cycler (PTC-100, MJ
Research, Watertown, MA). The temperature-time sequence of 95°C for
30 s, 58°C for 30 s, and 72°C for 1 min was carried out for
each PCR cycle. Primer sequences, optimal PCR cycles, and product sizes
of specific cDNA regions are shown in Table
1.
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Cytofluorometric analysis.
To study cell surface expression of MHC class
IA molecules, TC3,
TC6-F7,
and P388D1 macrophages were seeded
at a density of 2 × 105 in
35-mm tissue culture dishes (Corning) in DMEM (25 mM glucose) supplemented with 15% HS plus 2.5% FC. On reaching ~70%
confluence, cultures were exposed to fresh DMEM without or with IFN-
(100 U/ml) or IFN-
(50 U/ml) for 3 days. After cytokine treatment, cells were collected with an enzyme-free cell dissociation buffer (GIBCO) for immunostaining and subsequent flow cytometric analysis. Briefly, 1 × 106 cells were
incubated on ice in 50 µl of fluorescence-activated cell sorter
(FACS) buffer (PBS and 1% BSA) with saturating concentrations of
anti-pan MHC class I monoclonal antibody (M1-42; Ref. 38; The Jackson
Laboratory, Bar Harbor, ME) for 30 min. Cells were then washed twice
and incubated with 10 µg/ml of anti-rat IgG-phycoerythrin conjugate
(Jackson ImmunoResearch Laboratories, West Grove, PA) in 50 µl of
FACS buffer at 4°C for 30 min. After a final wash, cells were
resuspended in 1 ml of FACS buffer. Fluorescence intensity was
quantified by flow cytometry using an Epics 752 flow cytometer (Coulter, Hialeah, FL) equipped with an argon ion laser. Data were
analyzed with ELITE software from Coulter.
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RESULTS |
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Effects of IFN- or IFN-
on insulin
secretion and intracellular content in glucose-stimulated
TC6-F7 cells.
Routine microscopic inspection of
TC6-F7 cells did not reveal
readily distinguishable morphological changes in cultures treated for
up to 3 days with either IFN-
or IFN-
. Likewise, IFN treatment did not affect cell viability, as indicated by comparable protein and
DNA concentrations in cultures treated without or with IFN-
or
IFN-
(Table 2).
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Effects of IFN- or IFN-
on
Ifn-
6 mRNA expression by
TC6-F7 cells and P388D1
macrophages.
Ifn-
mRNA expression in islets is
an early pathological feature of autoimmune diabetes in humans and in
rodent models of type 1 diabetes (16, 17, 37). However, neither the
cellular origin of IFN-
within islets nor its modes of regulation
have been established (12). Accordingly, the expression of
Ifn-
mRNA in
TC6-F7 cells
without or with IFN-
or IFN-
treatment was studied and compared
with the control P388D1 macrophage
cell line. Among possible Ifn-
mRNAs, the expression of Ifn-
6 mRNA was chosen because this mouse gene locus has been conclusively demonstrated to encode a biologically active protein (15, 19, 44).
RT-PCR analysis demonstrated that
Ifn-
6 mRNA was expressed constitutively by both P388D1
macrophages and
TC6-F7 cells (Fig. 2).
Furthermore, steady-state Ifn-
6
mRNA expression by P388D1 macrophages or
TC6-F7 cells was not altered by IFN-
or IFN-
treatment (Fig. 2).
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Effects of IFN- or IFN-
on
expression of class IA MHC antigen
processing and antigen presentation genes by
TC6-F7
cells and P388D1 macrophages.
The ability of IFN-
(100 U/ml) and IFN-
(50 U/ml) to individually
modulate the expression of the class
IA MHC antigen-processing and
antigen presentation genes in
TC6-F7 cells vs.
P388D1 macrophages was compared by
Northern blot analysis. Laser densitometric analysis indicated that
IFN-
treatment increased H-2K
-chain and
2m mRNA expression by
TC6-F7 cells 5-fold and 10-fold compared with untreated controls
(3.3 ADU without IFN-
vs. 16.3 ADU with IFN-
for
H-2K
-chain; 1.4 ADU without
IFN-
vs. 14 ADU with IFN-
for
2m; Fig.
3). Treatment of
P388D1 macrophages with IFN-
upregulated H-2K
-chain and
2m mRNA expression eightfold
compared with untreated controls (1 ADU without IFN-
vs. 8.3 ADU
with IFN-
for H-2K
-chain; 1.5 ADU without IFN-
vs. 8 ADU with IFN-
for
2m; Fig. 3). Similar
to the effects of IFN-
, steady-state expression of H-2K
-chain and
2m mRNA by
P388D1 macrophages was increased after 3 days of IFN-
treatment (Fig. 3). In contrast, IFN-
treatment of
TC6-F7 cells did not significantly alter the
steady-state level of H-2K
-chain
or
2m mRNA expression after 3 days
of cytokine exposure (2 ADU without IFN-
vs. 3 ADU with IFN-
for
H-2K
-chain; 1.4 ADU without
IFN-
vs. 1.4 ADU with IFN-
for
2m; Fig. 3).
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Cell surface expression of MHC class IA
molecules in response to IFN- or IFN-
.
Cell surface expression of MHC class
IA molecules on
P388D1 macrophages,
TC3, and
TC6-F7 cells in response to IFN-
or IFN-
was compared. Basal
cell surface expression of MHC class
IA was observed for
P388D1 macrophages and for both
-cell lines in the absence of IFN treatment (Fig.
5,
A-C).
Basal MHC class IA cell surface
expression was higher for P388D1
macrophages compared with either of the
-cell lines (Fig. 5,
A-C).
Treatment with IFN-
(50 U/ml) for 3 days approximately doubled MHC
class IA cell surface expression
on P388D1 macrophages and
increased MHC class IA expression
by two orders of magnitude on each of the
-cell lines compared with
untreated control cultures (Fig. 5, G-I).
After IFN-
treatment, a similar level of fluorescence intensity for
surface MHC class IA staining was
observed for P388D1 macrophages and the two
-cell lines (Fig. 5,
G-I).
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DISCUSSION |
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This investigation demonstrates that IFN- but not IFN-
directly
diminishes insulin production and induces expression of the MHC class
IA antigen presentation pathway in
pancreatic
-cells. The demonstration of comparable IFN-
and
IFN-
upregulation of MHC class
IA expression in macrophages
further indicates that these two IFNs may play distinct roles in the
insulitic process.
A limited number of studies have analyzed the direct effects of IFN-
on
-cell phenotype and function. Rhodes and Taylor (33) demonstrated
that treatment of isolated human islets with high doses of IFN-
(1,000 U/ml) inhibits the synthesis of proinsulin. However, those
authors indicate that the high dose of IFN-
used may have reduced
total protein biosynthesis, as demonstrated with other cell types (33).
The present data and our previous report (2) conclusively demonstrate
that low doses of IFN-
decrease insulin production by pancreatic
-cell lines without altering total protein biosynthesis or
compromising cell viability. The more differentiated
TC6-F7 cells
are more susceptible than
TC3 cells to the inhibitory effects of
IFN-
, indicating that
-cells that maintain normal glucose
responsiveness may be more sensitive to this cytokine (not shown). That
possibility may provide an important clue in the search for mechanisms
by which IFN-
compromises
-cell insulin production. To date,
those mechanisms remain undefined. Available evidence indicates that
IFN-
inhibits processes that occur after preproinsulin gene
transcription but before insulin secretory granule exocytosis (Ref. 2;
unpublished observations).
Consistent with previous observations, IFN- treatment of
-cells
upregulated expression of the MHC class
IA pathway (2, 13). In contrast,
IFN-
treatment did not affect the basal level of cell surface class
I MHC expression or mRNA expression of the H-2K
-chain,
2m, or the endoplasmic reticulum
peptide transporter genes (Tap-1 and
Tap-2). That IFN-
increased
Lmp-2 and
Lmp-7 mRNA expression by
TC6-F7
cells and markedly upregulated MHC class
IA expression by
P388D1 macrophages indicates that
an effective dose of a biologically active IFN-
was used in the
present study. The differential response of the
-cell lines to
IFN-
vs. IFN-
is consistent with evidence that these two
cytokines bind to distinct cell surface receptors and activate
different DNA-binding proteins (8, 11, 25, 27-29). Despite their
candidacy as key insulitic cytokines, little is know about IFN-
or
IFN-
response pathways in
-cells.
Treatment of "purified" islet cell preparations from human islets
(30) with either IFN- or IFN-
increased cell surface MHC class
IA expression (30), with IFN-
having a greater stimulatory effect than IFN-
. The IFN-
reagent
used in those studies was derived from medium conditioned by Namalwa
cells, and quantitative data is not provided for IFN-
stimulation of
MHC class I expression, making it difficult to relate those results to
the current study, which evaluated responses specifically in
-cells
and used lower doses of a recombinant IFN-
product. In a more recent
study with isolated human islets, both IFN-
and IFN-
induced
TAP-1 protein and mRNA expression (41). Furthermore, a correlation was
observed for cytokine enhancement of TAP-1 and human leukocyte antigen (HLA) class I expression in both isolated islets and the human HP62
pancreatic endocrine cell line (41). In agreement with the earlier
study (41) and partially in agreement with the present results, IFN-
was shown to be a more potent stimulator of both TAP-1 and HLA class I
expression than IFN-
when individual effects of those cytokines were
compared, even with the use of a relatively large dose (500 U/ml) of a
recombinant IFN-
product. Nonetheless, apparently on the basis of
those results and the clear evidence for IFN-
expression in
pancreases from newly diagnosed patients with type 1 diabetes (12, 17,
37), those authors predict that IFN-
is "most probably" the
important cytokine among those capable of inducing cell surface HLA
class I expression on
-cells (41). The present results bring into
question that postulate, although differences in cytokine
responsiveness between mouse and human islet cells may well exist that
would invalidate a direct comparison between species.
Despite clear evidence for IFN- expression in islets from newly
diagnosed patients with type 1 diabetes (12, 17, 37), the cellular
origin of IFN-
within islets has not been conclusively defined.
Foulis et al. (12) localized IFN-
in insulin-containing cells via
immunocytochemistry; however, that observation does not prove
-cell
expression. Accordingly, our study provides the additional contribution
of demonstrating constitutive Ifn-
6
mRNA expression by a differentiated
-cell line. Neither IFN-
nor IFN-
modulated basal Ifn-
6 mRNA
expression in either
TC6-F7 cells or
P388D1 macrophages. Further
studies are required to determine the potential of exogenous cytokines
to modulate IFN-
secretion from
-cells.
Although it is demonstrated that IFN- does not directly induce major
phenotypic or functional changes in
-cells, those results do not
necessarily argue against an important role for this cytokine in
insulitis. Indeed, the demonstration of IFN-
expression by
-cells
enables possible clarification of the contributions of both IFN-
and
IFN-
during prediabetes. From clear evidence for IFN-
expression
in islets of patients with type 1 diabetes, it has been suggested that
local expression of IFN-
in response to potential diabetogenic
stimuli such as viruses may trigger the insulitic process (12, 16, 17,
37). In that regard it will now be important to identify exogenous
stimuli capable of modulating
-cell IFN-
expression. In support
of its role as an initiating agent, IFN-
has been shown to induce
intercellular adhesion molecule 1 (ICAM-1) and HLA class
IA on endothelial cells from human
islets (6). Increased expression of ICAM-1 and HLA class
IA by endothelial cells may
contribute to leukocyte infiltration during insulitis. Furthermore,
IFN-
facilitates T cell stimulation by the induction of the
costimulatory molecules ICAM-1 and B7.2 on antigen-presenting cells in
islets (5). IFN-
also stimulates natural killer cells and Th1
lymphocyte responses (18, 26, 43). Together with previous data, the
present results support the possibility that early IFN-
expression
by
-cells may be a critical event in the initiation of autoimmune
diabetes (5, 16, 17).
The observation that IFN-, but not IFN-
, directly affects the
phenotype and function of pancreatic
-cells agrees with the notion
that IFN-
plays a direct pathogenic role in autoimmune diabetes (23,
40, 42). We suggest that, in susceptible individuals, early expression
of IFN-
by the
-cell may contribute to insulitis, whereas
IFN-
, a product of islet-infiltrating leukocytes, may mediate
characteristic decreases in glucose sensitivity and increased cell
surface expression of MHC class IA
in the prediabetic
-cell, thereby magnifying the insulitic process.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases grant DK-49192 (to H. R. Gaskins). Mouse
recombinant IFN- was provided by Genentech (South San Francisco, CA), and human recombinant IFN-
-A/D was provided by Hoffmann-La Roche (Nutley, NJ).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: H. R. Gaskins, University of Illinois at Urbana-Champaign, 1207 W. Gregory Dr., Urbana, IL 61801.
Received 21 January 1998; accepted in final form 23 March 1998.
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