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Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104
Address all correspondence and requests for reprints to: John A. Corbett, Saint Louis University School of Medicine, Department of Biochemistry and Molecular Biology, 1402 South Grand Boulevard, St. Louis, Missouri 63104. E-mail: corbettj{at}wpogate.slu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B (NF-B). Heat
shock prevents IL-1- induced NF-B nuclear localization by
inhibiting inhibitory protein B (IB) degradation in rat islets.
Similar to rat islets, heat shock (stimulated by 90 min incubation at
42 C) prevents IL-1 + interferon 
-induced iNOS expression and
NF-B nuclear localization in human islets. IL-1 also stimulates
heat-shock protein 70 (hsp 70) expression by rat islets, and hsp 70
expression is dependent on islet production of nitric oxide. Last,
evidence is presented that implicates nitric oxide as a stimulus for
the expression of proteins that participate in islet recovery from
nitric oxide-mediated damage. These studies indicate that heat shock
prevents cytokine-induced islet damage by inhibiting iNOS expression,
and suggest that nitric oxide is one effector molecule that stimulates
the expression of factors involved in ß-cell recovery from nitric
oxide-mediated damage. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-) +
tumor necrosis factor (TNF) results in the expression of iNOS,
increased production of NO (9), and an inhibition of insulin secretion
(10). NMMA prevents cytokine-induced nitrite production and attenuates
the inhibitory effects on insulin secretion, suggesting that NO
mediates, in part, the inhibitory actions of cytokines on human islet
function (10). NO participates in cytokine-induced inhibition of
insulin secretion by targeting and inhibiting the enzymatic activities
of mitochondrial iron-sulfur-containing enzymes, specifically aconitase
and the electron transport chain at complexes I and II (6, 11).
Treatment of rat or human islets with IL-1ß or IL-1ß + IFN-,
respectively, results in a potent inhibition of aconitase that is
completely prevented by NMMA (12). The inhibitory effects of IL-1 on islet mitochondrial aconitase activity and insulin secretion are reversible. Rat islets incubated with IL-1ß for 15 h require a 4-day incubation in cytokine-free media to recover normal glucose-stimulated insulin secretion (13, 14). The recovery of islet secretory function can be reduced to 8 h by the inhibition of iNOS. The addition of NMMA to islets pretreated for 18 h with IL-1ß, followed by an 8 h incubation in the presence of both IL-1ß and NMMA, results in complete recovery of insulin secretion (15). The recovery of insulin secretion correlates with a simultaneous recovery of mitochondrial aconitase activity. In addition, the recovery of islet metabolic function is prevented by the transcriptional inhibitor, actinomycin D (12, 15). These findings suggest that NO, IL-1, or both, stimulate the expression of yet to be identified proteins that participate in islet recovery from NO-mediated damage.
Islets exposed to heat shock appear to be resistant to cellular death
induced by NO donor compounds (16). Heat-shock protein (hsp) 70 is one
member of the heat-shock family of proteins whose expression is highly
induced under conditions of cellular stress (17). Kolb and co-workers
(18) showed that overexpression of hsp 70 prevents RINm5F cell lysis in
response to sodium nitroprusside. Cytokines have also been shown to
stimulate hsp 70 expression by rat islets, however the mechanism of
cytokine-induced hsp 70 expression is unknown (19, 20). In addition,
the effects of heat shock on IL-1-induced iNOS expression and NO
production by islets have not been examined. In this study we show that
heat shock prevents iNOS expression and nitrite production by rat and
human islets by inhibiting cytokine-induced activation of the
transcriptional regulator NF-B. In addition, evidence is presented
that implicates NO as the stimulus for IL-1-induced hsp 70 expression
by rat islets.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-32P]Deoxycytidine triphosphate and
enhanced chemiluminescence reagents were purchased from Amersham Pharmacia Biotech (Arlington Heights, IL). NF-B consensus
oligonucleotide and rabbit anti-IB- antiserum were purchased from
Santa Cruz Biotechnology, Inc. (Santa Cruz, CA).
Horseradish peroxidase-conjugated donkey antirabbit IgG was obtained
from Jackson ImmunoResearch Laboratories, Inc. (West
Grove, PA). Rabbit antiserum specific for the C-terminal 27 amino acids
of mouse macrophage iNOS was a gift from Dr. Thomas Misko (G.D. Searle & Co., St. Louis, MO). iNOS and cyclophilin cDNAs were
gifts from Dr. Charles Rodi (Monsanto Corporate Research, St. Louis,
MO) and Dr. Steve Carroll (Department of Pathology, University of
Alabama-Birmingham), respectively. Collagenase type XI was purchased
from Sigma Chemical Co. (St. Louis, MO). RPMI 1640,
CMRL-1066, penicillin, streptomycin, and human recombinant IFN- were
from Gibco BRL (Grand Island, NY). FCS was obtained from
Hyclone Laboratories, Inc. (Logan, UT). Human recombinant
IL-1ß was obtained from Cistron Biotechnology (Pine
Brook, NJ). NMMA was purchased from Calbiochem (San Diego,
CA). All other reagents were from commercially available sources.
Islet isolation and culture
Islets were isolated from 250–300 g male Sprague-Dawley rats
(Harlan Sprague Dawley, Inc., Indianapolis, IN) by
collagenase digestion as described previously (21). After isolation,
islets were cultured overnight in complete CMRL-1066 media (CMRL-1066
media supplemented with 2 mM L-glutamine, 10%
heat-inactivated FCS serum, 100 U/ml penicillin, and 100 µg/ml
streptomycin) under an atmosphere of 95% air and 5% CO2
at 37 C.
Heat shock
The heat-shock response was induced in RINm5F cells and isolated
rat and human islets by culturing for 30, 60, or 90 min at 42 C,
respectively. The islets and cells were then incubated at 37 C for an
additional 3 h to allow for recovery from heat shock. Unless
otherwise indicated, experiments were initiated by the addition of 1
U/ml IL-1 for RINm5F cells and rat islets or 75 U/ml IL-1 + 750 U/ml
IFN- for human islets.
Nitrite formation
Nitrite formation was measured by mixing 50 µl culture media
with 50 µl Griess reagent (22). The absorbance was measured at 540
nm, and nitrite concentrations were calculated from a sodium nitrite
standard curve.
Glucose-stimulated insulin secretion
Following cytokine stimulation, islets were washed three times
with Krebs-Ringer bicarbonate buffer (25 mM HEPES, 115
mM NaCl, 24 mM NaHCO3, 5
mM KCl, 1 mM MgCl2, and 2.5
mM CaCl2, pH 7.4) containing 3 mM
D-glucose and 0.1% BSA. Groups of 20 islets were counted
into 10 mm x 75 mm borosilicate tubes and preincubated for 30 min
in 200 µl of the same buffer at 37 C with shaking. The preincubation
solution was removed, and glucose-stimulated insulin secretion was
initiated by the addition of 200 µl Krebs-Ringer bicarbonate buffer
containing either 3 mM or 20 mM
D-glucose. Islets were incubated for 30 min, incubation
media was removed, and insulin content was determined by RIA (23).
Islet dispersion
Isolated islets (
1000/condition) were dispersed into
individual cells by treatment with trypsin (1 mg/ml) in
Ca+2- and Mg+2-free Hanks solution at 37
C for 3 min as described previously (12). The dispersed islets were
counted, plated (1 x 106 cells/ml of complete
CMRL-1066), and allowed to incubate overnight before initiation of
experiments.
Aconitase activity
Heat shocked and control RINm5F cells (5 x 106
cells/2 ml complete CMRL-1066) were incubated in the presence or
absence of 1 U/ml IL-1ß and 0.5 mM NMMA for 18 h.
Dispersed rat islets (1 x 106 cells/2 ml complete
CMRL-1066) were incubated for 1 h with the NO donor compound,
sodium (Z)-1(N, N-diethylamino) diazen-1-ium-1,2-diolate (DEA-NO), in
the presence or absence of actinomycin D, or incubated for 1 h
with DEA-NO, then washed three times with complete CMRL-1066 to remove
the DEA-NO, and cultured for an additional 5 h in the presence or
absence of actinomycin D. After culture, the cells were isolated by
centrifugation, and mitochondrial aconitase activity was measured at
340 nm as described previously (6, 12).
Western blot analysis
Following cytokine treatment, islets were washed three times in
0.1 M PBS, pH 7.4. The islet pellet was dissolved in 20
µl SDS sample mix (0.25 M Tris-HCl, 20%
ß-mercaptoethanol, and 4% SDS) and 10 µl H2O and
boiled for 4 min. Proteins (10 µg/lane) were separated on 10%
SDS-polyacrylamide gels by the method of Laemmli (24) and transferred
to nitrocellulose membranes under semidry transfer conditions. Blots
were blocked in TBST (20 mM Tris, 500 mM NaCl,
and 0.1% Tween 20, pH 7.5) containing 5% nonfat dry milk overnight at
4 C and then incubated for 1.5 h at room temperature with rabbit
antihuman IB- (1:5000 dilution), mouse antirat hsp 70 (1:2000
dilution), rabbit antimouse iNOS (1:2000 dilution), or rabbit antihuman
iNOS (1:800 dilution) in TBST containing 1% nonfat dry milk as
indicated. The blots were then washed three times with TBST for 5 min
per wash, followed by incubation with horseradish peroxidase-conjugated
donkey antirabbit or donkey antimouse secondary antibody (1:5000
dilution) for 40 min. The blots were washed three times with TBST
followed by target protein detection by enhanced chemiluminescence
(Amersham Pharmacia Biotech).
Northern blot analysis
Control or heat-shocked islets (1000 islets/condition) were
incubated for 6 h in the presence or absence of 1 U/ml IL-1ß at
37 C. The islets were isolated by centrifugation, washed three times
with 0.1 M PBS, and total RNA was isolated using the RNeasy
kit (Qiagen, Chatsworth, CA). Total RNA (5–10 µg) was
denatured and fractionated by gel electrophoresis using a 1.0% agarose
gel containing 2.2 M formaldehyde. RNA was transferred by
capillary action to a Duralon UV nylon membrane
(Stratagene, La Jolla, CA), and the membrane was then
hybridized to a 32P-labeled DNA probe for rat iNOS or
cyclophilin. The probe was radiolabeled with
[-32P]deoxycytidine triphosphate by random priming
using the Prime-a-Gene nick translation system from Promega Corp. (Madison, WI). iNOS DNA corresponds to bases 509-1415 of
rat iNOS coding region. Cyclophilin was used as an internal control for
RNA loading. Hybridization and autoradiography were performed as
described previously (25, 26).
Nuclear extraction and gel shift analysis
Nuclear proteins were extracted from 1 x 106
dispersed islet cells using previously described methods (27). Protein
concentrations were determined by the Pierce bicinchonic
acid-microassay (Pierce Chemical Co., Rockford,
IL). Double-stranded synthetic oligonucleotide probe for NF-B was
end labeled using [-32P]ATP and T4 polynucleotide
kinase (Promega Corp.). Binding reactions contained 10
µg nuclear extracts, 0.5–1 ng oligonucleotide probe, 2 µg/ml
poly(dI-dC) (Boehringer Mannheim, Indianapolis, IN) in a
buffer containing 20 mM HEPES, pH 7.8, 50 mM
NaCl, 1 mM DTT, 1 mM EDTA, and 5% glycerol and
incubated for 20 min at 30 C. DNA and protein complexes were resolved
on 4% Tris-glycine nondenaturing polyacrylamide gels using a
Tris-glycine buffer system (0.05 M Tris-HCl, pH 8.3, 0.38
M glycine, 2 mM EDTA, 28). After
electrophoresis, gels were dried and exposed to photographic film.
Statistical analysis densitometry and image analysis
Statistical comparisons were made between groups using a one-way
ANOVA. Significant differences between groups were determined by
Scheffé’s F test poct hoc analysis. Autoradiograms
were scanned using a COHU high-performance charged coupled
device camera (Brookfield, WI), and densities were determined using NIH
Image version 1.59 software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The iNOS inhibitor NMMA completely
prevents IL-1-induced nitrite production (data not shown) and hsp 70
expression by rat islets. These results indicate that IL-1-induced hsp
70 expression requires the endogenous production of NO by rat islets.
To confirm that NO stimulates hsp 70, rat islets were treated with or
without the NO donor compound DEA-NO for 1 h. As shown in Fig. 1b, DEA-NO (500 µM) stimulates the expression of hsp 70 by
rat islets. We also compared the effects of IL-1 and heat shock on hsp
70 expression by rat islets (Fig. 1a). Islets subjected to a 60-min
incubation at 42 C (heat shock) express 5.6 ± 1.6-fold higher
levels of hsp 70 than the levels stimulated by IL-1 (quantitated by
densitometry), and neither IL-1 nor NMMA further modulate hsp 70
expression following heat shock (6.6 ± 1.3 and 6.4 ±
2.3-fold increases above IL-1-induced hsp 70 expression,
respectively).
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). However, IL-1 fails to
stimulate iNOS mRNA accumulation in rat islets pretreated for 60 min at
42 C before cytokine stimulation. Similar to the inhibitory effects of
heat shock on IL-1-induced iNOS mRNA accumulation, islets pretreated
for 60 min at 42 C before IL-1 stimulation fail to express iNOS at the
protein level (Fig. 2b) or to produce nitrite (Fig. 2c). The inhibitory
effects of heat shock on IL-1-induced iNOS expression do not appear to
be associated with heat-shock-induced inhibition of protein synthesis.
IL-1-induced iNOS mRNA expression does not require de novo
protein synthesis (28, 30), and [35S]methionine
incorporation is nearly identical in control and rat islets treated for
60 min at 42 C before IL-1 stimulation (data not shown). These findings
indicate that heat shock prevents cytokine-induced iNOS expression and
nitrite production by rat islets at sites upstream of IL- 1-induced
iNOS mRNA expression.
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B degradation and NF-B
nuclear translocation by rat isletsB activation and nuclear localization is one signaling event
associated with IL-1-induced iNOS expression by rat islets (28, 31, 32). Because heat shock inhibits IL-1-induced iNOS expression by rat
islets, the effects of heat shock on NF-B activation was evaluated
by gel shift analysis. Treatment of rat islets for 30 min with IL-1ß
stimulates the nuclear localization of NF-B as shown by the reduced
mobility of the NF-B and DNA probe complex (Fig. 3a). However, NF-B nuclear
localization is attenuated in islets pretreated for 60 min at 42 C
before IL-1 stimulation. The specificity of the NF-B/DNA interaction
was confirmed by inhibition of complex formation in the presence of
100-fold excess unlabeled NF-B oligonucleotide DNA (data not shown).
Also, inclusion of antiserum specific for NF-B (p65) in the binding
reaction further retards the migration of the NF-B and DNA complex
(supershift; data not shown). These findings indicate that one
mechanism by which heat shock prevents IL-1-induced iNOS expression by
rat islets is by the inhibition of IL-1-induced NF-B nuclear
localization.
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B is found in the cytoplasm as an inactive
heterodimer of p50/p65 subunits bound to the inhibitory protein, IB.
Upon stimulation, IB is phosphorylated on specific serine residues
that target IB for degradation (33). To determine whether heat shock
inhibits NF-B nuclear localization by preventing IL-1-induced IB
degradation, the effects of a 60-min incubation at 42 C on IL-
1-induced IB degradation by rat islets were examined. Treatment
of rat islets for 30 min with IL-1ß results in complete degradation
of IB (Fig. 3b
). However, IL-1-induced IB degradation is
attenuated in rat islets subjected to heat shock before cytokine
stimulation. These findings suggest that heat shock inhibits
cytokine-induced NF-B nuclear localization by a mechanism that
involves the inhibition of IB degradation.
Protective effects of heat shock on IL-1-induced inhibition of
mitochondrial aconitase activity and glucose-stimulated insulin
secretion
The mechanism by which IL-1 inhibits glucose-stimulated insulin
secretion involves the expression of iNOS by ß-cells followed
by NO-mediated inhibition of ß-cell oxidative metabolism (1, 29, 30). Therefore, if heat shock prevents IL- 1-induced
iNOS expression, it should also prevent the damaging effects of IL-1 on
aconitase activity and insulin secretion by rat islets. Treatment of
rat insulinoma RINm5F cells for 18 h with 1 U/ml IL-1 results in a
potent inhibition of mitochondrial aconitase activity that is
completely prevented by coincubation with NMMA (Fig. 4a). However, IL- 1 fails to
inhibit aconitase activity of RINm5F cells preincubated under
heat-shock conditions (30 min at 42 C: conditions that stimulate
hsp 70 expression and prevent IL- 1-induced iNOS
expression; data not shown) before incubation with IL-1.
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). IL-1-induced inhibition of insulin
secretion is prevented if islets are pretreated for 60 min at 42 C
before cytokine stimulation. However, heat-shocked islets release
higher levels of insulin in response to both 3 mM and 20
mM glucose as compared with non–heat-shocked islets.
Although heat shock increases insulin secretion, the fraction of
insulin secreted in response to 20 mM glucose as compared
with 3 mM glucose is nearly identical whether or not the
islets were heat shocked (Fig. 4b, percent of control, hatched
bars). The mechanism by which heat shock increases the levels of
insulin secretion in response to basal and stimulatory concentrations
of glucose is unknown. It is possible that heat shock stimulates islet
damage resulting in leakage of insulin from islets; however, this
interpretation is not likely, because heat shock does not inhibit
mitochondrial aconitase activity (Fig. 4a) or induce morphological
damage to islets (as determined by phase contrast microscopic analysis;
data not shown).
Effects of heat shock on cytokine-induced NF-B activation and
iNOS expression by human islets
Previous studies have shown that IL-1 and IFN- are the minimal
combination of cytokines required to stimulate iNOS expression by human
islets (34). Treatment of human islets for 40 h with IL-1 +
IFN- results in iNOS expression as determined by Western blot
analysis (Fig. 5a). IL-1 +
IFN--induced iNOS expression is markedly reduced if human islets are
pretreated for 90 min at 42 C before cytokine stimulation. The
mechanism by which heat shock attenuates IL-1 + IFN--induced iNOS
expression appears to be associated with the inhibition of
cytokine-induced NF-B activation. Incubation of human islets for 30
min with IL-1ß + IFN- results in NF-B nuclear localization as
evidenced by the reduced mobility of a DNA probe containing the
consensus sequence for NF-B binding (Fig. 5b). However, IL-1 +
IFN- fails to stimulate NF-B nuclear localization in human islets
heat shocked for 90 min at 42 C before cytokine stimulation. These
findings, which are similar to the effects of heat shock on
IL-1-induced iNOS expression by rat islets, indicate that heat shock
prevents IL-1 + IFN--induced iNOS expression by human islets by a
mechanism that is associated with the inhibition of NF-B nuclear
localization.
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suggests that NO mediates IL-1-induced hsp 70 expression by rat islets.
Therefore, we examined the effects of actinomycin D on recovery of
aconitase activity in islets treated with NO. In these experiments,
islets were either treated with DEA-NO for 1 h, washed, and
aconitase activity determined, or the islets were treated with DEA-NO
for 1 h, washed three times to remove the NO donor compound, and
cultured for an additional 5 h in the absence of DEA-NO. The
islets were then isolated and aconitase activity was determined.
Treatment of rat islets for 1 h with the NO donor compound DEA-NO
results in an approximate 65% inhibition of mitochondrial aconitase
activity (Fig. 6, solid bars).
Islets completely recover aconitase activity to control levels if the
islets are washed to remove the NO donor compound and incubated for an
additional 5 h in the absence of DEA-NO (Fig. 6, hatched
bars). Incubation of rat islets with the transcriptional inhibitor
actinomycin D during the 5-h recovery period (in the absence of DEA-NO)
prevents islet recovery of mitochondrial aconitase activity. The
inhibitory effects of actinomycin D on the recovery of aconitase
activity are not due to an inhibition of constitutive mRNA expression,
because actinomycin D does not inhibit islet aconitase activity during
a 5-h incubation (Fig. 6). These findings suggest that NO directly
inhibits islet mitochondrial aconitase activity, and that NO also
stimulates the expression of factors that participate in the recovery
from NO-mediated damage.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B is
required for IL-1-induced iNOS expression by rat islets (28, 32). We
show that heat shock prevents IL-1-induced IB degradation and
NF-B nuclear localization in rat islets. Heat shock also inhibits
cytokine-induced iNOS expression by human islets of Langerhans. Human
islets preincubated under heat-shock conditions (90 min at 42 C) do not
express iNOS in response to IL1 + IFN-. Similar to rat islets, heat
shock prevents IL-1 + IFN--induced NF-B activation and nuclear
localization. These findings indicate that heat shock provides
functional protection against the damaging effects of IL-1 by
preventing iNOS expression by rat islets. In addition, these studies
provide the first evidence that heat shock prevents cytokine-induced
expression of human iNOS (human islets), by inhibiting NF-B nuclear
localization.
Although our studies are not capable of discerning whether the
protective actions of heat shock are mediated by increased hsp 70
expression or additional biochemical changes associated with heat shock
(17), human islets constitutively express high levels of hsp 70 (36),
and hsp 70 expression does not appear to be further altered by heat
shock or IL-1 + IFN- treatment (data not shown). The findings that
human islets expressing constitutively high levels of hsp 70 (in the
absence of heat shock; data not shown) still express iNOS in response
to IL-1 + IFN-, whereas heat shock prevents IL-1 + IFN--induced
NF-B nuclear localization and iNOS expression by human islets,
suggest that the inhibitory effects of heat shock on cytokine-induced
iNOS expression may be independent of hsp 70. The heat-shock response
has been shown to prevent cytokine-induced iNOS expression by rat
astrocytes, rat hepatocytes, and murine lung epithelial cells (37, 38, 39).
In addition, Kim et al. (40) showed that hsp 70 expression
protects hepatocytes from TNF-induced apoptosis. The protective actions
of the heat-shock response are associated with the inhibition of
NF-B activation and nuclear localization. Heat shock may prevent
NF-B activation by either inhibiting IB degradation (37),
stimulating IB expression (41), or both. Although our studies do not
discriminate between these two possibilities, the net result of each
event is the sequestering of NF-B in the cytoplasm and the
inhibition of NF-B-dependent mRNA transcription. A putative
heat-shock element in the IB promoter region has been identified,
and the heat-shock response has been shown to stimulate IB
expression and inhibit TNF-induced IB degradation in A549 lung
adenocarcinoma cells (41). The heat-shock response may also inhibit
cytokine signaling at sites upstream of NF-B activation. Gabai
et al. (42) showed that heat shock prevents the activation
of stress-activated Jun N-terminal kinase (JNK). In addition, IL-1
stimulates JNK activation in RINm5F cells (43); however, the effects of
heat shock on IL-1-induced JNK activation and the role of JNK in
IL-1-induced iNOS expression by RINm5F cells have not been examined. We
are currently examining the potential role of JNK in IL-1-induced iNOS
expression, and whether heat shock prevents JNK activation in rat
islets.
Islets also have the ability to recover from NO-mediated damage, and this recovery process is dependent on de novo mRNA transcription; however, the stimulus that induces the expression of potential recovery factors has yet to be identified (12, 15). We show that a 1-h incubation with the NO donor compound DEA-NO results in the inhibition of islet mitochondrial aconitase activity. Islets completely recover normal aconitase activity if DEA-NO is removed by washing, and the islets are allowed to recover for an additional 5 h. The transcriptional inhibitor actinomycin D inhibits the recovery of islet aconitase activity. These results indicate that NO stimulates the expression of factors that participate in islet recovery from NO-mediated damage. We also show that IL-1-induced hsp 70 expression is inhibited by NMMA, and that DEA-NO stimulates hsp 70 expression by rat islets. These findings suggest that hsp 70 may be one potential protein that is expressed in response to NO and that participates in islet recovery from NO mediated islet damage.
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Acknowledgments |
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Footnotes |
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2 Supported by a Career Development Award from the Juvenile Diabetes
Foundation International.
Received May 12, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B (NF-B) and induce nitric oxide
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P < 0.05.
