Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Madrid, and Instituto "Reina Sofía" de Investigaciones Nefrológicas, CSIC, 28006 Madrid, Spain
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ABSTRACT |
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Nitric oxide (NO) and cGMP may exert positive or negative
effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1 plus tumor necrosis factor (TNF)-
reduced iNOS levels, while
NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS
protein and mRNA levels. This suggests that NO may contribute both to
iNOS induction and downregulation. Soluble guanylyl cyclase (sGC)
activation may be involved in these effects. Inhibition of sGC
attenuated IL-1
/TNF-
-elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of
transcription unveiled a negative posttranscriptional modulation of the
iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.
inflammatory mediators; human mesangial cells; mRNA stability; nitric oxide; inducible nitric oxide synthase; guanosine 3',5'-cyclic monophosphate
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INTRODUCTION |
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GLOMERULAR MESANGIAL
CELLS are specialized smooth muscle cells that contribute to the
structural support of the glomerulus and to the control of glomerular
filtration rate. They also play an important role in the pathological
processes of the glomerulus, particularly in glomerulonephritis and
glomerulosclerosis (24). On exposure to proinflammatory
agents, these cells become activated and express increased levels of
adhesion molecules, like intercellular adhesion molecule 1 and vascular
cell adhesion molecule 1, and generate cytokines, prostaglandins, and
nitric oxide (NO) (24). The increased generation of NO
associated with glomerular inflammation is due in part to the
expression of the inducible form of nitric oxide synthase (iNOS). The
induction of iNOS in mesangial cells has been documented in vitro
(36) as well as in human glomerulonephritis (9). The role of NO in glomerular disease is not fully
elucidated (see Ref. 34 for review). NO may exert
protective effects by inhibiting the increased production of
extracellular matrix, which is associated with the progression of
glomerulonephritis (17). However, high levels of NO can be
deleterious due to cytotoxic effects (13). The existence
of glomerular mechanisms to terminate the production of NO is suggested
by the increased expression of negative regulators of iNOS expression
like interleukin (IL)-13, IL-4, and transforming growth factor-
(TGF-
) in glomerulonephritis (2, 16, 20, 28). In
addition, NO itself has been proposed to participate in the negative
control mechanisms regulating its own synthesis (5, 12,
29).
NO has been reported to modulate both the activity and expression of iNOS. A negative feedback of NO on NOS enzymatic activity has been previously attributed to the ability of NO to interact with the heme component of the enzyme (1, 12). In addition, NO has been shown to modulate iNOS expression. However, the nature of the effects encountered appears to depend on the experimental system under study. In smooth muscle and rat mesangial cells stimulated with IL-1, NO has been proposed to play a positive role in iNOS induction (3, 25). In contrast, NO donors have been reported to limit iNOS induction in glial cells (29) and in macrophages (30). Generation of cGMP by activation of soluble guanylyl cyclase (sGC) has been implicated in mediating some of the effects of NO donors on gene expression (8, 33, 38, 41). With regard to iNOS, cGMP-elevating agents have been reported to exert either positive or negative effects on iNOS induction in a cell type-dependent manner. Whereas atrial natriuretic factor and cell-permeable cGMP analogs amplify iNOS induction in smooth muscle cells (14), the same agents inhibit iNOS expression in murine macrophages (15).
In this work, we have used human mesangial cells to explore the role of NO and cGMP in the modulation of iNOS expression. We have observed that both NO donors and cGMP analogs can exert either stimulatory or inhibitory effects on iNOS expression in a time-dependent fashion.
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MATERIALS AND METHODS |
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Materials.
Recombinant human TNF- was a generous gift of Dr. J. M. Redondo
(Centro de Biología Molecular, CSIC). Recombinant human IL-1
(5 × 107 U/mg) was from Boehringer Mannheim.
Recombinant human TGF-
1 was from R&D Systems Europe (Abingdon, UK).
Cell culture media and fetal bovine serum were from Bio-Whittaker.
-[32P]dCTP (3,000 Ci/mmol) was from Amersham
(Buckinghamshire, UK). Antibodies for immunoblotting were monoclonal
anti-iNOS (Transduction Laboratories,), polyclonal anti-iNOS, sc-651
(Santa Cruz Biotechnology, Santa Cruz, CA), polyclonal anti-TGF-
1
(Promega, Madison, WI), and peroxidase-conjugated anti-mouse and
anti-rabbit immunoglobulins (Dako, Glostrup, Denmark).
1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) was from Alexis (Laüfelfingen, Switzerland).
3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was from
Calbiochem (San Diego, CA). All other reagents used were of the highest
purity available from Sigma (St. Louis, MO).
Cell culture. Human mesangial cells (HMC) were obtained and characterized as previously described (36). For experiments, cells from three independent preparations between passages 5 and 15 were used. Confluent HMC were incubated in RPMI without phenol red with the indicated agents in the absence of serum. Cell viability, as evaluated by trypan blue exclusion, was above 90% under all experimental conditions studied.
Nitrite determination. The accumulation of nitrite in the cell culture supernatant of HMC was taken as an index of iNOS activity. After treatment with the various agents, nitrite was measured in the supernatants of HMC by the Griess reaction as previously described (36), by using sodium nitrite as a standard.
RNA isolation and Northern blot analysis.
Total cellular RNA was isolated from HMC by using the guanidinium
thiocyanate-phenol-chloroform method (4). Ten micrograms of total RNA were separated on 1% agarose/0.68 M formaldehyde gels,
transferred to MSI magnagraph membranes (Westborough, MA), and
ultraviolet (UV) cross-linked with a UV Stratalinker 1800 (Stratagene,
La Jolla, CA). For analysis of iNOS mRNA expression, a 2.1-kb fragment
from the human iNOS cDNA, a gift of Dr. D. A. Geller (10),
was labeled with -[32P]dCTP by using the kit Rediprime
for random primer labeling from Amersham. A 2.4-kb fragment of human
TGF-
1 (gift of Dr. J. Egido, Fundación Jiménez
Díaz, Madrid, Spain) labeled as above, was used to assess
TGF-
1 mRNA levels. Hybridization was performed at 42°C for 16 h. Membranes were then washed at final stringency conditions of 1×
standard sodium citrate (SSC), 0.5% SDS at 42°C, and exposed to
X-OMAT S Kodak film at
80°C. To ensure even loading of the samples,
blots were stripped and rehybridized with a probe for the 28 S rRNA
gene (pTRI RNA 28S) from Ambion (Austin, TX). Densitometric analysis
was performed by using an Agfa StudioStar TPO scanner with the public
domain software NIH IMAGE 1.60b5. Results were calculated as the ratio
of iNOS mRNA to 28 S rRNA expression.
Determination of iNOS mRNA
half-life.
HMC were stimulated with IL-1/tumor necrosis factor (TNF)-
for
4 h in the presence or absence of 8-bromo-cGMP (8-BrcGMP). For
determination of iNOS mRNA half-life, actinomycin D (10 µg/ml) was
subsequently added and cells were then harvested for RNA isolation and
Northern blot analysis every 2 h for 8 h as described above.
SDS-PAGE and immunoblotting. For analysis of iNOS protein expression, HMC were harvested by treatment with trypsin-EDTA. Cell extracts were obtained and analyzed by Western blot as described (6, 37). Blots were probed with anti-iNOS antibody (1:1,000 dilution) followed by secondary antibody at 1:2,000 dilution, and the iNOS band was visualized by using an enhanced chemiluminiscence (ECL) detection system from Amersham. Levels of iNOS protein were estimated by densitometry of the ECL exposures as previously described (6), and the values obtained were corrected by the band intensities of the Coomassie staining of membranes after the blotting procedure.
Data analysis. Unless otherwise indicated, data are expressed as means ± SE obtained in at least three separate experiments. Comparisons were made with analysis of variance followed by Dunnett's modification of the t-test, whenever comparisons were made with a common control and the unpaired two-tail Student's t-test for other comparisons. The level of statistically significant difference was defined as P < 0.05.
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RESULTS |
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Characterization of iNOS induction in
HMC.
Induction of iNOS activity in HMC occurs in response to the stimulation
with combinations of cytokines or of cytokines plus bacterial
lipopolysaccharide (LPS) (36). Under our experimental conditions, levels of iNOS protein assessed by Western blot showed a
good correlation with the induction of iNOS activity as estimated from
the accumulation of nitrite in the cell culture supernatant (Fig.
1A). In subsequent experiments
HMC were stimulated with a combination of IL-1/TNF-
. This
cytokine combination elicited a submaximal induction of iNOS protein
(Fig. 1A, bottom). Levels of iNOS mRNA were
undetectable in unstimulated cells (Fig. 1B). In cells
stimulated with IL-1
/TNF-
, iNOS mRNA could be detected after a
4-h treatment and reached maximal levels between 8 and 12 h. After
12 h, iNOS mRNA levels started to decline but remained elevated
above basal levels up to at least 24 h (Fig. 1B).
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Effect of NOS inhibitors and NO
donors on iNOS expression in HMC.
To assess the importance of NO generation for iNOS induction, we
stimulated HMC with IL-1/TNF-
in the presence of the NOS inhibitors nitro- L-arginine methyl ester
(L-NAME) and N-monomethyl-L-arginine (L-NMMA) or the NO donors sodium nitroprusside (SNP) and
S-nitroso-N-acetylpenicillamine (SNAP). At 500 µM, L-NAME reduced cytokine-induced NO generation by 88%
(Fig. 2A). This effect was
associated with a 56 ± 3% reduction of iNOS protein levels
(mean ± SE of three experiments), assessed after an 8-h treatment
(Fig. 2B). A similar effect was observed when
L-NMMA was used as NOS inhibitor. Supplementation of HMC with a single dose of SNP at the time of stimulation with cytokines resulted in an accumulation of nitrite in the cell culture supernatant that was more than additive with respect to the amounts generated by
cells treated only with cytokines or with SNP (Fig. 2A).
This suggested a positive role of SNP on iNOS induction. In fact, both SNP and SNAP clearly amplified iNOS protein expression at 8 h (3.2 ± 0.6-fold amplification in the case of SNP,
n = 3) (Fig. 2B). None of the NO donors or
NOS inhibitors elicited iNOS expression per se (not shown).
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Effect of ODQ and cGMP analogs on
iNOS expression elicited by
IL-1/TNF-
.
It is well known that IL-1
/TNF-
-induced NO generation activates
sGC in glomerular mesangial cells (GMC) (23, 32).
Therefore, we explored the potential involvement of sGC activation and
cGMP generation in the amplifying effects of endogenous and exogenous NO. Treatment of HMC with IL-1
/TNF-
for 8 h in the presence of the sGC inhibitor ODQ at 1 µM resulted in lower levels of iNOS protein (41 ± 5% reduction, n = 3) (Fig.
4A). This suggests that the
integrity of the NO/cGMP pathway is important for iNOS induction. ODQ
also reduced iNOS induction in SNP-supplemented cells (40.5 ± 7.2% reduction, n = 3). In keeping with this, the cell
permeable analogs of cGMP, 8-BrcGMP, and dibutiryl-cGMP, amplified
IL-1
/TNF-
-elicited iNOS induction in a dose-dependent manner
(Fig. 4B). A clear amplification of iNOS induction was
observed even with the lowest dose of 8-BrcGMP employed (3.4 ± 0.7-fold potentiation of iNOS protein levels in cells stimulated for
8 h in the presence of 10 µM 8-BrcGMP with respect to the levels
found in cells treated with cytokines alone, n = 3).
This effect was associated with a twofold increase in nitrite formation
(control: 2 ± 0.4; cytokines: 7 ± 0.9; cytokines plus 10 µM 8-BrcGMP: 13.3 ± 0.6 pmol of nitrite/106 cells,
P < 0.05 vs. cytokines; n = 7). An
amplification of iNOS activity was also evident when HMC were
stimulated with cytokines in the presence of the NO-independent
activator of sGC, YC-1 (26) at 20 µM for 24 h
(2.2 ± 0.3 amplification of nitrite accumulation, n = 4). None of the cGMP analogs elicited iNOS
expression per se. These results suggest that cGMP generation may
contribute to the stimulatory effect of NO donors on iNOS expression.
To study the predominance of the effects of NO and cGMP, the
potentiating effect of 8-BrcGMP was assessed in the presence of
L-NAME and/or ODQ. Neither inhibitor reduced the amplifying
effect of 8-br-cGMP on iNOS protein expression (Fig. 4C)
thus suggesting that cGMP supplementation could overcome the effect of
the inhibition of iNOS and of sGC.
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Effect of donors and inhibitors of NO/cGMP
generation on the decay of iNOS mRNA.
To gain insight into the mechanisms underlying the diverse effects of
NO and cGMP donors on cytokine-elicited iNOS induction, we evaluated
their potential influence on iNOS mRNA stability. For this purpose, HMC
stimulated for 4 h with IL-1/TNF-
alone or in combination
with various modulators of the NO/cGMP pathway, were treated with
actinomycin D to inhibit further transcription, and 8 h later the
amount of iNOS transcript remaining was assessed by Northern blot. As
it can be observed in Fig. 6, inhibition of the NO/cGMP pathway with either L-NAME or ODQ resulted
in a higher proportion of iNOS mRNA remaining after actinomycin D
treatment than that observed in cytokine-treated cells in the absence
of inhibitors. In contrast, supplementation with 8-BrcGMP accelerated iNOS mRNA decline. These observations suggest that the NO/cGMP pathway
may exert a negative regulation of iNOS expression at a
posttranscriptional level.
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8-BrcGMP reduces iNOS
mRNA stability.
To characterize the effect of cGMP donors, the half-life of iNOS mRNA
from HMC that had been treated with IL-1/TNF-
alone or in
combination with 8-BrcGMP for 4 h, was determined after the
addition of actinomycin D (Fig. 7). We
observed that 8-BrcGMP significantly shortened iNOS mRNA half-life,
from 7.9 ± 1.0 to 4.0 ± 0.3 h (P < 0.05 by t-test). Thus 8-BrcGMP can exert a negative effect
on cytokine-elicited iNOS mRNA levels by acting at a
posttranscriptional level. The half-life of iNOS mRNA as herein
determined is within experimental error of the values previously
reported by us (37) and in agreement with those measured
by other authors in different experimental systems (7,
11), although in a number of studies a shorter half-life for the
iNOS transcript has been observed (19, 42). From these and
other studies it appears that the stability of iNOS mRNA may be cell
type, stimulus, and/or time dependent.
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DISCUSSION |
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The NO/cGMP pathway has been reported to modulate the steady-state
levels of various transcripts in different cell types. Among the gene
products modulated by NO/cGMP are TNF-, cyclooxygenase-2 (COX-2),
c-fos, c-jun, sGC, and cGMP-dependent kinase
(8, 14, 33, 38, 41). The existence of autocrine or
paracrine mechanisms involving NO and/or cGMP that may control NO
synthesis through the modulation of iNOS expression has been proposed
in several reports (14, 15, 25). Both an amplification and
an inhibition of iNOS expression by NO generation have been observed
(25, 29). Based on the published evidence, it could be
hypothesized that the prevalence of positive or negative effects is
cell type and/or species dependent. Thus in smooth muscle and mesangial cells, NO donors and/or cGMP-elevating agents appear to play a positive
role on iNOS expression (3, 14, 25), whereas in macrophage-type cells the effect most frequently encountered is negative (15, 29, 30). Here we show that both types of
effects can be evidenced in the same experimental system in a
time-dependent fashion. The observation that NOS inhibitors limit iNOS
induction by a combination of IL-1
/TNF-
indicates that the
endogenous generation of NO is important for iNOS induction by
proinflammatory stimuli. Moreover, the experiments performed in the
presence of NO donors and cGMP analogs unveil a potentiation of iNOS
expression at early stages of activation. However, both types of agents
show a predominantly inhibitory effect at later treatment times. It could be hypothesized that in the initial stages of an inflammatory process NO can amplify its own synthesis, but at the same time it can
contribute to trigger or amplify mechanisms that result in a negative
feedback modulation of iNOS expression.
The mechanisms by which NO brings about these effects may be multiple.
NO and cGMP have been reported to modulate gene expression by
posttranscriptional mechanisms. In smooth muscle cells, NO donors and
cGMP analogs have been shown to reduce the stability of the transcripts
of sGC (8) and cGMP-dependent kinase-I (38). In the case of human iNOS, a number of recent reports emphasize the
importance of posttranscriptional mechanisms in determining the extent
and duration of iNOS induction (27, 35). However, as far
as we know, an effect of NO or cGMP analogs on iNOS mRNA stability has
not been reported previously. The reduction of iNOS mRNA half-life in
the presence of cGMP analogs, described in our study, suggests the
existence of a novel level of regulation of iNOS expression by the
NO/cGMP pathway. iNOS mRNA destabilization by cGMP could contribute to
the limitation of iNOS induction observed at late treatment times in
cells supplemented with NO or cGMP donors. The events leading to a
reduction of the iNOS transcript half-life in cGMP-supplemented cells
are presently under study. NO and cGMP have been reported to influence
the synthesis of cytokines that in turn may be able to reduce iNOS mRNA
stability, like TGF- and TNF-
(14, 39, 43). Results
from our laboratory indicate that cGMP supplementation may induce an
amplification of cytokine-elicited TGF-
1 transcript and
immunoreactive TGF-
in HMC-conditioned media (Pérez-Sala D,
Cernuda-Morollón E, Díaz-Cazorla M, and Lamas S,
unpublished observations). Thus it could be hypothesized that TGF-
may contribute to the increased degradation of the iNOS transcript
observed in the presence of cGMP analogs.
The events underlying the early amplifying effect of NO donors and cGMP
analogs on iNOS protein and mRNA levels remain to be elucidated. The
results herein presented do not exclude the participation of
transcriptional mechanisms in these effects. NO donors have been
previously reported to augment the rate of transcription of iNOS in rat
mesangial cells stimulated with IL-1 (25). Potential
targets of NO and cGMP are the transcription factors activator
protein-1 (AP-1) and nuclear factor (NF)-
B, which play an important
role in the induction of iNOS in response to cytokine stimulation
(22, 40). NO-releasing agents and cGMP analogs have been
shown to increase AP-1-DNA binding and transcriptional activity in rat
embryo fibroblasts (33). However, we have not observed
changes in AP-1 DNA binding activity of nuclear extracts from HMC
supplemented with 8-BrcGMP during cytokine stimulation (results not
shown). NO- and cGMP-elevating agents have also been reported to
modulate the activity of NF-
B either in a positive (18,
21) or in a negative manner (15, 31). We have
recently described that NO donors can exert both types of effects on
I
B
expression in HMC, leading to increased nuclear translocation of NF-
B at the initial stages of stimulation with IL-1
/TNF-
and decreased nuclear levels of NF-
B at later times, and this is
associated with a biphasic modulation of COX-2 expression
(6). Thus the modulation of I
B
levels may also play
a role in the regulation of iNOS expression by NO. In contrast,
8-BrcGMP did not elicit detectable changes in cytokine-induced NF-
B
nuclear translocation or in I
B
expression (Pérez-Sala D,
Cernuda-Morollón E, Díaz-Cazorla M, and Lamas S,
unpublished results). These and previous observations (3, 6, 30,
31) suggest that NO can modulate NF-
B activation by
cGMP-independent mechanisms.
In summary, our results suggest the existence of autocrine pathways by which NO and/or cGMP generation appear to control iNOS expression. This control involves positive and negative feedback mechanisms that determine the amplitude of iNOS induction. These and previous observations illustrate a multifunctional role of the NO/cGMP pathway in HMC because it may contribute both to the onset and to the limitation of the response of HMC to proinflammatory stimuli.
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ACKNOWLEDGEMENTS |
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We are indebted to the transplant coordination team from Hospital 12 de Octubre, Madrid, Spain, for supplying us with kidneys unsuitable for transplantation.
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FOOTNOTES |
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This work was supported by grants from CICYT (SAF97-0035 and SAF2000-0149), Comunidad Autónoma de Madrid (CAM) Grant 08.4/0032/1998, and a grant-in-aid from the Spanish Society of Nephrology. M. Díaz-Cazorla and E. Cernuda-Morollón were recipients of a fellowship from Instituto "Reina Sofía" de Investigaciones Nefrológicas (Spain).
Address for reprint requests and other correspondence: D. Pérez-Sala, Centro de Investigaciones Biológicas, CSIC, Velázquez, 144, 28006 Madrid, Spain (E-mail: dperezsala{at}cib.csic.es).
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. Section 1734 solely to indicate this fact.
Received 17 March 2000; accepted in final form 1 November 2000.
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