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-Induced Interferon Regulatory Factor-1 (IRF-1) Expression in Rodent and Human Islet Cells Precedes Nitric Oxide Production1
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden (M.F., D.L.E.) and Department of Metabolism and Endocrinology, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium (D.L.E.)
Address all correspondence and requests for reprints to: Malin Flodström, Department of Medical Cell Biology, Uppsala University, Box 571, S-751 23 Uppsala, Sweden. E-mail: malin.flodstrom{at}medcellbiol.uu.se
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß are required for expression of
the enzyme nitric oxide synthase (iNOS), and NO production by human
pancreatic islets. In this study, possible mechanisms by which IFN-
participates in iNOS messenger RNA (mRNA) expression were evaluated in
both rodent and human islets cells. Addition of IFN-, before or
after arrest of IL-1ß-induced iNOS gene transcription by actinomycin
D, did not prolong iNOS mRNA half life in the rat insulin-producing
cell line RINm5F (RIN cells). IFN- also failed to modify
IL-1ß-induced activation of the transcription factor 
B (NF-B)
in RIN cells, as determined by electrophoretic mobility shift assay.
However, IFN- induced an early (30 min–1 h) increase in interferon
regulatory factor-1 (IRF-1) mRNA expression and a later (2 h) 19-fold
increase in RIN cell nuclear IRF-1 protein content, an effect further
potentiated by IL-1ß. The total cellular content of IRF-1 protein
increased by 30- to 50-fold in human islets exposed for 2–8h to
IFN- or IFN- + IL-1ß. IL-1ß alone induced a marginal and
transient increase in IRF-1. It has been previously reported that
nicotinamide prevents IL-1ß-induced IRF-1 expression in rat
pancreatic islets. However, nicotinamide (20 mM) presently
failed to prevent IL-1ß + IFN--induced IRF-1 protein expression in
human pancreatic islets. In conclusion, the effects of IFN- on iNOS
expression can neither be explained by iNOS mRNA stabilization nor
increased NF-B activation. However, IFN- induces an early
increase in cellular IRF-1 content, and this may contribute to
increased iNOS mRNA expression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF-) and interferon- (IFN-). In human
islet preparations, it is necessary to use a combination of two to
three cytokines (i.e. IL-1ß + IFN- or IL-1ß + IFN-
+ TNF-) to induce NO formation (5) and the role for NO in
cytokine-induced human ß-cell dysfunction still remains unclear.
Thus, while one study indicates that NO mediates cytokine-induced human
ß-cell dysfynction (6), three other studies showed dissociation
between NO production and the deleterious effects of cytokines (7, 8, 9, 10).
Even if the amount of NO produced by human islet endocrine cells may
not be enough to harm these cells, there are other possible sources for
NO production during insulitits, namely activated macrophages (11, 12)
and islet capillary endothelial cells (13). The combined production of
NO by mononuclear cells, endothelial cells, and the endocrine cells may
generate enough NO to damage human ß-cells (14), emphasizing the need
to further understand regulation of iNOS expression in endocrine and
nonendocrine islet cells.
Cellular NO production may be regulated by transcriptional and
posttranscriptional events, such as expression and stability of iNOS
messenger RNA (mRNA) and protein (5), as well as by the availability of
substrate and cofactors (15). It has been previously shown that
activation of the transcription factor NF-B is a necessary step for
cytokine-induced iNOS mRNA expression and NO formation both in insulin
producing cell lines rodent and human islets (16, 17, 18, 19). However, IL-1ß
alone induces nuclear NF-B binding but fails to stimulate NO
production in human islets (19). Thus, while activation of NF-B
seems to be sufficient to induce iNOS expression in rodent islets,
other factors are probably needed for iNOS expression in human islets.
Because IFN-, in combination with IL-1ß, is required for human
iNOS induction, it is conceivable that some of these factors are
induced by IFN-.
Interferon regulatory factor-1 (IRF-1), a transcription factor
activated in response to IFN-, is indispensable for IFN-- or
LPS-induced expression of the iNOS gene in murine macrophages (20).
Recently, it was shown that IL-1ß induces IRF-1 mRNA expression and
NO production in rat islets, and that both phenomena were prevented by
high concentrations of nicotinamide (20 mM) (21). Unlike
NF-B, which is present in the cytosol bound to an inhibitory subunit
I-B (22), IRF-1 has to be synthesized de novo (23).
Considering that protein synthesis is necessary for iNOS mRNA
expression in insulin producing cells (5), it is conceivable that IRF-1
is one of the newly synthesized proteins involved in iNOS expression.
Besides the putative effects of IFN- on iNOS mRNA expression
discussed above, the cytokine may also increase iNOS mRNA stability, as
described for murine macrophages (24).
In the present study, we examined IFN- actions on NF-B and IRF-1
activation and the potential posttranscriptional effects of the
cytokine on iNOS mRNA stability in the insulin producing cell line
RINm5F. Some of these experiments were also reproduced in rat and human
pancreatic islets.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(bioactivities of 6.7 and 10 U/ng, respectively) were purchased
from AMS Biotechnology (Täby, Sweden). The cytokine
concentrations used in this study were derived from data previously
obtained in RINm5F cells (25), rat (26), and human pancreatic islets
(8). Human IL-1ß was used in both human and rat experiments.
Chemicals were purchased from the following sources: culture medium
RPMI-1640 (containing 0 or 11 mM glucose) and FCS,
Northumbria Biologicals (Irvine, UK); collagenase from
Clostridium histolyticum, Boehringer-Mannheim (Mannheim,
Germany); agarose, FMC Bioproducts (Rockland, ME); MagnaGraph Nylon
Transfer Membrane, Micron Separation (Westboro, MA); nitrocellulose
filters, Schleicher & Schuell (Dassel, Germany). Double-stranded
oligomers for electrophoretic mobility shift assay (EMSA) were produced
by Dr. J. Seibt (Department of Immunology, Uppsala University, Uppsala,
Sweden) and labeled with [-32P]-deoxy-CTP using the
Megaprime DNA labeling kit, Amersham International (Aylesbury, UK). All
other chemicals of analytical grade were obtained from E. Merck
(Darmstadt, Germany) or Sigma.
Tissue culture
Human islets were isolated from pancreata retrieved from 14
heart-beating organ donors sent to the Central Unit of the ß-Cell
Transplant, Brussels as previously described (27). The age of the
donors (mean ± SEM) was 32 ± 4 yr (range 8–61
yr). Aliquots of the preparations were examined by electron microscopy
(n = 14), indicating less than 0.5% exocrine cells. The
prevalence of insulin- and glucagon-positive cells was determined by
light microscopical examination of immunohistochemically stained islets
(28), showing 46.5 ± 3.8% insulin-positive cells and 11.4
± 2.0% glucagon-positive cells. After isolation, islets were cultured
in Brussels for 3–16 days (8 ± 1 days) (29) before being sent by
air to Uppsala (27). Adult male Sprague Dawley rats (local colony,
Biomedical Centre, Uppsala, Sweden) were housed, fed, and cared for
according to the guidelines of the Swedish Regulations for Animal Care.
All experiments involving rat tissue were approved by the Ethical
Committee on Animal Experiments, Uppsala, Sweden. Rats were killed by
cervical dislocation under ether anesthesia and islets isolated by
collagenase digestion. Islets were cultured for to 2–4 days before
experiments. In Uppsala, both human and rat islets were cultured
free-floating in RPMI-1640 medium containing 10% (vol/vol) FCS,
benzylpenicillin (100 U/ml), streptomycin (0.1 mg/ml), and either 5.6
(human islets) (8, 27) or 11 mM glucose (30). Medium was
changed every second day.
The insulinoma cell line RINm5F, originally provided by Professor Å. Lernmark (then at the Hagerdorn Institute, Copenhagen, Denmark), was trypsinized and subcultured in medium RPMI-1640 supplemented with 10% (vol/vol) FCS, benzylpenicillin (100 U/ml), streptomycin (0.1 mg/ml) (25). Experiments were performed when cells reached 60–80% confluence.
Nitrite determination
The presence of nitrite, a stable product of NO reacting with
molecular oxygen, in the culture mediums was determined with the Griess
reagent (31). Thus, 10 µl of freshly prepared reagent, consisting of
0.5% naphtylethylenediamin dihydrochloride, 5% sulphanilamide and
25% concentrated H3PO4, was added to
triplicate aliquots of culture medium (100 µl). After incubation for
two min at 60 C, the absorbance of the reaction product was measured
spectrophotometrically at 546 nm. A standard curve of sodium nitrite
was used to calculate nitrite concentrations.
Northern blot analyses and studies of mRNA stability
For the Northern blotting, total RNA was extracted from 5
x 106 RINm5F cells using the RNeasy-kit (Qiagen, Hilden,
Germany). Equal amounts of RNA (20–30 µg) were then
electrophoretically separated on 1% agarose gels containing 2.2
M formaldehyde. After acridine orange staining of gels, to
control for similar sample loadings, the RNA was transferred to a nylon
membrane and the Northern blots hybridized to
[32P]-labeled complementary DNAs (cDNAs) coding for mouse
macrophage iNOS (a kind gift from Dr. J. M. Cunningham,
Hematology-Oncology Division, Harvard Medical School, Boston, MA) or
human IRF-1 (kindly provided by Dr. H. Ueda, Molecular and Cellular
Biology Department; Nippon Boehringer Ingelheim Co. Ltd., Kawanishi,
Japan). Membranes were subsequentially hybridized to cDNA encoding
human glyceraldehyde 3-phosphate dehydrogenase (GAPDH, American Type
Culture Collection, Rockville, MD), used as an internal control. GAPDH
mRNA expression is unaffected by different stages of cell growth in
distinct cell lines (32), or by acute IL-1ß exposure in
insulin-producing and rat islets (33). The hybridization and
autoradiography were performed as previously described (33, 34). The
autoradiograms were subjected to densitometric scanning using the Quick
Scan Jr. densitometer (Helena Laboratories, Beaumont, TX) and expressed
in arbitrary units of OD. In all experiments, iNOS or IRF-1 ODs were
corrected by values of GAPDH OD.
For iNOS mRNA stability studies, cells were initially exposed to
IL-1ß (25 U/ml) or IL-1ß (25 U/ml) + IFN- (1000 U/ml) for 6
h, to achieve maximal iNOS mRNA expression (25). Cells were then washed
and fresh medium containing actinomycin D (act D, 5 mg/ml) added to
arrest transcription. In some experiments, IFN- was added together
with act D. Cells were harvested after 0, 2, 4, and 6 h and iNOS
mRNA contents analyzed by Northern blot (see above).
Nuclear protein extraction and EMSA
3–5 x 106 RINm5F cells were exposed to
cytokines for 20–60 min (19). Nuclear protein was extracted and
NF-B binding activity in the protein fractions was determined by
EMSA as previously described in (19). A double-stranded 26 mer
oligonuclotide containing the B binding site
5'-AGCTTCAGAGGGGACTTTCCGAGAGG was labeled with [32P] dCTP
and used for the EMSA. A 100-fold excess of nonlabeled oligonucleotide
was used as a negative control. The samples were then separated on 5%
nondenaturing polyacrylamide gels, exposed to film, and the band
intensities quantified by densitometric scanning with a Quick Scan Jr.
densitometer. OD values were corrected for the amount of loaded
protein, determined with Bradford reagent (35).
Western blot analysis
Groups of 60 rat or 100–150 human islets were exposed to
cytokines and/or nicotinamide (20 mM) for 2–8 h, washed
twice in cold PBS, pelleted by centrifugation, and sonicated for 10 sec
in 100 µl cold TE (10 mM Tris, 1 mM EDTA)
containing 0.5 mM phenylmethylsulfonylfluoride. One aliquot
was taken for total protein content determinations (35), and the
remaining lysate was precipitated with two volumes of cold acetone.
Protein was pelleted by centrifugation (10 min at 12 000 rpm) and
solubilized in SDS-gel sample buffer (2% SDS; 100 mM Tris,
pH 6.8; 100 mM ß-mercaptoethanol; 0.01% bromophenol
blue; 10% glycerol) by boiling for 4 min. Equal amounts of protein
(10–20 µg) were then run on 9% SDS-polyacrylamide gels and
transferred to nitrocellulose filters. The same method was used for
immunoblotting of nuclear proteins extracted from RINm5F (for
extraction of nuclear proteins see above). Filters were preblocked with
5% fat-free milk powder before incubation with antibodies against rat
or human IRF-1 (Santa Cruz Biotechnology, CA) diluted 1:400 in PBS +
5% fat-free milk powder. Horse-radish peroxidase (HRP) linked goat
antirabbit Ig was used as a secondary antibodies. Immunodetection was
then performed using the ECL immunoblotting detection system (Amersham
International, Aylesbury, UK). Band intensities were quantified from
non saturated exposures using the Quick Scan Jr densitometer.
Statistical analysis
Results are presented as means ± SEM. Data
were compared using Student’s unpaired or paired t test.
When multiple comparisons were performed, the data were evaluated by
ANOVA, followed by group comparisons with Student’s t test
and correction of P values for multiple comparisons by the
Bonferroni method (36). In the experiments with human pancreatic
islets, results obtained from each donor were considered as one
individual observation, even when experiments were performed in
duplicate or in triplicate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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on IL-1ß-induced iNOS expression were
due to a synergistic effect on NF-B activation (Fig. 1
). Densitometric scanning of the autoradiographs showed
an 55-fold increase in binding activity after exposure to IL-1ß alone
(control, 82 ± 33; IL-1ß, 4531 ± 489; P
< 0.001 vs. control; n = 3), but no increase after
exposure to IFN- (IFN-, 101 ± 50; n = 3). Moreover,
IFN- did not potentiate IL-1ß effects on NF-B binding (increase
compared with control: IL-1ß alone, 70-fold; IL-1ß + IFN-,
72-fold; n = 2). When exposure time was extended to 60 min,
IFN- again failed to activate or further increase IL-1ß induced
NF-B nuclear binding (data not shown). Thus, IFN- neither
activates NF-B nor potentiates the stimulatory effect of IL-1ß on
this transcription factor.
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alone failed to increase
nitrite levels (1.0 ± 0.3 pmol NO2-/µg
DNA x h, n = 6), but it potentiated IL-1ß effects
(148 ± 29, n = 6; P < 0.01 vs.
both control and cells exposed to IL-1ß alone; ANOVA).
To test whether IFN- alters the stability of iNOS mRNA, RINm5F cells
were treated either with IL-1ß alone or IL-1ß + IFN- for 6
h, and transcription then arrested by actinomycin D (act D, Fig. 2). A similar 40–70% decline in iNOS mRNA expression
was observed 2–6 h after act D addition in both IL-1ß and IL-1ß +
IFN--treated cells. In a second series of experiments, cells were
exposed to IL-1ß alone for 6 h, and then act D added with or
without IFN-. Again, there was a rapid decline in iNOS mRNA levels
already after 2 h (IL-1ß, 73%; IL-1ß + IFN-, 51% of
control; n = 2; experimental conditions as in Fig. 2), followed by
further decrease after 4 and 6 h (4 h, 56 and 40%; 6 h, 33
and 28% of control, respectively for IL-1ß and IL-1ß + IFN-).
These observations suggest that IFN- does not potentiate
IL-1ß-induced iNOS expression by increasing mRNA stability.
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), cytokines induced a clear increase in IRF-1 mRNA
expression already after 30 min, with a peak after 1 h. To further
evaluate this phenomenon, we performed additional experiments where
RINm5F cells were exposed for 1 h to cytokines (methods as in Fig. 3, data as OD corrected for GAPDH expression). IL-1ß and IFN-
induced respectively a 6- and 21-fold increase in IRF-1 mRNA expression
(n = 8; respectively P < 0.05 and
P < 0.01 vs. control; ANOVA), whereas the
combination of IL-1ß + IFN- induced a 68-fold increase in IRF-1
expression vs. control and an 11-fold increase compared with
cells treated with IL-1ß alone (n = 8; P < 0.01
both vs. control and cells treated with IL-1ß alone;
ANOVA).
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, A and B). A low basal expression of IRF-1 was
detected both in rat and human islets. In rat islets, IFN- induced a
4- to 5-fold increase in IRF-1 expression, an effect not further
increased by IL-1ß (4). In human islets (4), IFN- alone or in
conjunction with IL-1ß induced a marked increase in IRF-1 (32- to
40-fold above control levels). As observed for rat islets (4), IL-1ß
alone induced a small (4- to 6-fold) but nonsignificant increase of
IRF-1 content in human islets (4). In two experiments, human islet
IRF-1 contents were determined after longer exposure periods to
cytokines. IRF-1 expression was still slightly increased (6- to 7-fold
above control) after 4-h exposure to IL-1ß, with a return to basal
levels (1–2-fold above control) after 8 h, whereas in islets
treated with IFN- and IFN- + IL-1ß, IRF-1 levels were still
markedly elevated both after 4 h (52-to 53-fold above control) and
8 h (25- to 40-fold above control).
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alone increased basal medium nitrite contents (pmol/µg
DNA x h; control, 1.4 ± 0.7, n = 5; IL-1ß, 0.4
± 0.2, n = 5; IFN-, 0.4 ± 0.4, n = 4). On the other
hand, islets exposed to IL-1ß + IFN- produced 6- to 7-fold more
nitrite than control islets (9.0 ± 2.3 pmol/µg DNA x h, n
= 5; P < 0.05 vs. control, ANOVA).
Nuclear migration is a crucial event for IRF-1-induced gene
transcription. Thus, we next examined the appearance of IRF-1 in the
nuclear protein fractions of RINm5F cells exposed to IL-1ß and/or
IFN- for 2 h (Fig. 5). IL-1ß and
IFN- alone increased nuclear IRF-1 contents by respectively 3-fold
and 19-fold (compared with control), whereas IRF-1 contents in islets
exposed to a combination of IL-1ß + IFN- were 37-fold higher than
in control cells.
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(Fig. 6). Nicotinamide neither
effected basal IRF-1 protein expression nor prevented IL-1ß +
IFN--induced increase in IRF-1 expression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B (5). It has been previously shown that, whereas IL-1ß
is a sufficient stimulus for induction of iNOS mRNA expression and NO
production in the insulinoma cell line RINm5F and rat islets of
Langerhans, a combination of at least IL-1ß + IFN- is required to
induce NO formation by human islets ((5), and present data). It is
noteworthy that IL-1ß alone activates NF-B in human islets without
inducing iNOS activity (19). Thus, it is likely that additional
signal(s) provided by IFN- are required to increase expression of
the human iNOS gene.
Data obtained in other cell types suggest that putative sites for
IFN- action include stabilization of iNOS mRNA (24), potentiation of
IL-1ß-induced NF-B activation (37) and induction of other nuclear
transcription factors, such as IRF-1 (38). In the present study, we
observed that IFN- alone or in combination with IL-1ß and added
before or after transcriptional arrest by actinomycin D, did not
increase the stability of iNOS mRNA in RINm5F cells. Moreover, IFN-
did not potentiate IL-1ß-induced activation of the transcription
factor NF-B. However, IFN- or IFN- + IL-1ß induced an early
expression of the transcription factor IRF-1 in RINm5F cells, rat and
human islets. Moreover, this was followed by appearance of IRF-1
protein in the nucleus, an important step for IRF-1 action (23). To our
knowledge, this is the first demonstration that IFN- induces IRF-1
expression in human and rodent islet cells. Binding sequences for IRF-1
are present in the rat and human iNOS promoters (39, 40), and deletion
analysis in the rodent macrophage cell line RAW 264.7 suggests that
this factor regulates iNOS expression by binding to an interferon
response element (IRE) in the murine iNOS promoter (41). It is thereby
possible that IFN--induced IRF-1 expression plays a role for iNOS
mRNA expression in human pancreatic islets.
IRF-1 competes with IRF-2 for the binding to sequences found in the
promoters from IFN--responsive genes and is presently known to be a
key factor in regulation of cell growth and apoptosis (23).
IFN--induced IRF-1 gene expression involves activation of STAT-1
(Signal Transducers and Activators of Transcription-1) dimers and
their subsequent binding to GAS (gamma-activated sequence) elements in
the IRF-1 promoter. NF-B binding sequences are present both in the
human and rodent IRF-1 promoters, and NF-B may regulate IRF-1
transcription in response to other stimuli then IFN-,(42). Because
IL-1ß induces NF-B activation in both human and rodent islet cells
(17, 18), this may explain the presently observed marginal increase in
IRF-1 expression in cells exposed to IL-1ß alone. Interestingly,
IFN--induced IRF-1 mRNA levels in RINm5F cells are still increasing
after 2 h exposure, whereas there is already a decreased IRF-1
expression in cells stimulated with IL-1ß alone or in combination
with IFN- (Fig. 3
). In human islets, IFN- also evokes a stronger
and longer lasting effect on IRF-1 expression than IL-1ß. Moreover,
human islet cells present a higher increase in IRF-1 protein content
after exposure to IFN-, as compared with rat islet cells (Fig. 4).
Thus, if IRF-1 is indeed necessary for iNOS expression in human islets,
it is conceivable that the modest IRF-1 induction by IL-1ß (Fig. 4B)
is not sufficient to synergize with NF-B and trigger iNOS
expression. On the other hand, the marked increase in IRF-1 induced by
IFN- may be enough for, together with IL-1ß-induced NF-B
activation, the induction of iNOS mRNA. Clearly, future studies
blocking either IRF-1 expression or nuclear binding are required to
clarify this issue.
Nicotinamide, an inhibitor of poly (ADP-ribose) polymerase and, at high concentrations, a free radical scavenger, partially blocks cytotoxic effects of cytokines on rodent and human pancreatic islets (7, 10, 43, 44). It was recently shown that nicotinamide (20 mM) inhibits IL-1ß-induced IRF-1 mRNA expression and decreases NO production in rat pancreatic islets (21). Based on these data, it was concluded that these beneficial effects of nicotinamide are mediated via IRF-1 inhibition. However, our present data suggest that this is not the case for human pancreatic islets. Thus, 20 mM nicotinamide did not modify cytokine-induced IRF-1 in these cells.
Antibodies against IFN- prevents diabetes development in the NOD
mice, and the cytokine has been found in the insulitis lesion of NOD
mice and BB rats, reviewed in Ref. 2 . Besides the above described
effects of IFN- on iNOS expression, the cytokine affect the
expression of other proteins of potential relevance for ß-cell
destruction. Thus, IFN- alone or in combination with IL-1
up-regulate expression of MHC class I (45) and Fas (CD95 or Apo-1) (46)
in cultured rodent islets and anti-IFN--antibodies prevent
overexpression of MHC class I molecules in NOD mice (2). In other cell
types, expression of MHC class I and ß2-microglobulin is
coregulated by NF-B and members of the IRF-family (47). Thus, it may
be of interest to characterize the role of IRF-1 in the expression of
these genes in rodent and human pancreatic islets.
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Acknowledgments |
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Footnotes |
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Received February 11, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B in insulin producing RINm5F cells is
prevented by the protease inhibitor Na-p-tosyl-L-lysine
chloromethylketone. Biochem Biophys Res Commun 203:149–155[CrossRef][Medline]
B in the signaling mechanism. Endocrinology 136:4790–4795[Abstract]
B (NF-B) and induce nitric
oxide production in human pancreatic islets. FEBS Lett 385:4–6[CrossRef][Medline]
B. Annu Rev Cell Biol 110:405–455[CrossRef]
and glucose stimulate MHC class I
expression by human and rat pancreatic ß-cells. Diabetologia [Suppl
1]39:A101:378 (Abstract)
B in vitro and inhibits NF-B induction of
major histocompatibility class I and ß2-microglobulin gene expression
in transfected human neuroblastoma cells. J Neuroimmunol 63:157–162[CrossRef][Medline]
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 A. E. Karlsen, D. Pavlovic, K. Nielsen, J. Jensen, H. U. Andersen, F. Pociot, T. Mandrup-Poulsen, D. L. Eizirik, and J. Nerup Interferon-{gamma} Induces Interleukin-1 Converting Enzyme Expression in Pancreatic Islets by an Interferon Regulatory Factor-1-Dependent Mechanism J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 830 - 836. [Abstract] [Full Text]
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 S. T. Azar, H. Tamim, H. N. Beyhum, M. Z. Habbal, and W. Y. Almawi Type I (Insulin-Dependent) Diabetes Is a Th1- and Th2-Mediated Autoimmune Disease Clin. Vaccine Immunol., May 1, 1999; 6(3): 306 - 310. [Full Text] [PDF]
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V. Faure, C. Hecquet, Y. Courtois, and O. Goureau Role of Interferon Regulatory Factor-1 and Mitogen-activated Protein Kinase Pathways in the Induction of Nitric Oxide Synthase-2 in Retinal Pigmented Epithelial Cells J. Biol. Chem., February 19, 1999; 274(8): 4794 - 4800. [Abstract] [Full Text] [PDF]
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 D. C. Thompson, S. E. Porter, A. K. Bauer, K. C. Das, B. Ou, L. Dwyer-Nield, C. W. White, and A. M. Malkinson Cytokine-induced nitric oxide formation in normal but not in neoplastic murine lung epithelial cell lines Am J Physiol Lung Cell Mol Physiol, June 1, 1998; 274(6): L922 - L932. [Abstract] [Full Text] [PDF]
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N. Giannoukakis, W. A. Rudert, M. Trucco, and P. D. Robbins Protection of Human Islets from the Effects of Interleukin-1beta by Adenoviral Gene Transfer of an Ikappa B Repressor J. Biol. Chem., November 17, 2000; 275(47): 36509 - 36513. [Abstract] [Full Text] [PDF]
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A. K. Cardozo, H. Heimberg, Y. Heremans, R. Leeman, B. Kutlu, M. Kruhoffer, T. Orntoft, and D. L. Eizirik A Comprehensive Analysis of Cytokine-induced and Nuclear Factor-kappa B-dependent Genes in Primary Rat Pancreatic beta -Cells J. Biol. Chem., December 21, 2001; 276(52): 48879 - 48886. [Abstract] [Full Text] [PDF]
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A. E. Karlsen, S. G. Ronn, K. Lindberg, J. Johannesen, E. D. Galsgaard, F. Pociot, J. H. Nielsen, T. Mandrup-Poulsen, J. Nerup, and N. Billestrup Suppressor of cytokine signaling 3 (SOCS-3) protects beta -cells against interleukin-1beta - and interferon-gamma -mediated toxicity PNAS, October 9, 2001; 98(21): 12191 - 12196. [Abstract] [Full Text] [PDF]
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