(Hypertension. 1999;33:283-289.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Interleukin-1ß Regulation of the Human Brain Natriuretic Peptide Promoter Involves Ras-, Rac-, and p38 Kinase–Dependent Pathways in Cardiac Myocytes
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
Correspondence to Dr Margot C. LaPointe, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689. E-mail mclapointe{at}aol.com
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Abstract—Because both the brain natriuretic peptide (BNP) gene and the cytokine interleukin-1ß (IL-1ß) are induced in the infarcted myocardium, localized production of IL-1ß may regulate the BNP gene. We tested whether (1) IL-1ß regulates the human BNP promoter, (2) cis elements in the proximal promoter respond to IL-1ß, and (3) mitogen-activated protein kinase (MAPK) signaling pathways [p42/44, c-jun (JNK) and p38 kinase] are involved. We transferred the hBNP promoter coupled to a luciferase reporter gene or constructs with mutations in the proximal promoter GATA and M-CAT elements into neonatal rat ventricular myocytes and treated the cells with IL-1ß for 24 hours. IL-1ß–stimulated hBNP luciferase activity was eliminated by pretreatment with the transcription inhibitor actinomycin D. Both the p38 kinase inhibitor SB205380 (SB) and cotransfection of a dominant-negative mutant of p38 kinase reduced IL-1ß stimulation of the hBNP promoter. Dominant-negative mutants of Ras and Rac inhibited IL-1ß–stimulated hBNP luciferase activity by 64% and 90%, respectively. Constitutively active forms of Rac and MKK6, the immediate upstream activator of p38, were stimulatory; however, only the effect of MKK6 was inhibited by SB. Neither the p42/44 nor the JNK pathway was involved in the action of IL-1ß. Both IL-1ß and MKK6 activation of the hBNP promoter were partially reduced when the promoter contained a mutated M-CAT element. In summary, (1) IL-1ß is a transcriptional activator of the hBNP promoter; (2) IL-1ß acts through a Ras-dependent pathway not coupled to activation of p42/44 MAPK or JNK; (3) IL-1ß acts through a Rac-dependent pathway, but the downstream effector is not known; and (4) IL-1ß activation of p38 kinase is partially involved in regulation of the hBNP promoter, targeting the proximal M-CAT element.
Key Words: cell signaling • peptides, natriuretic • cytokines • M-CAT element
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Introduction |
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Human brain natriuretic peptide (hBNP), one of three members of the natriuretic peptide family, is composed of 32 amino acids and has diuretic, natriuretic, and vasodilator properties.1 BNP is synthesized and secreted constitutively by the ventricles of the heart throughout development, unlike atrial natriuretic peptide (ANP), which is expressed at a low level in adult ventricles except in pathophysiological conditions.1 2 As a consequence of acute myocardial infarction and heart failure, as well as other conditions characterized by left ventricular hypertrophy, plasma BNP can be elevated as much as 100- to 200-fold,2 3 suggesting that synthesis of BNP may play an important compensatory role in these diseases. In addition, plasma BNP levels can be used as a biochemical marker of heart dysfunction.3 4 5 6
Inflammatory cytokines such as interleukin-1ß (IL-1ß) are increased after myocardial infarction and during progression of heart failure.7 Thus IL-1ß is a potential regulator of the BNP gene in such pathophysiological conditions. In different types of cells, the effect of IL-1ß is mediated by stimulation of a mitogen-activated protein kinase (MAPK), in particular p38 kinase.8 9 10 Several MAPK pathways have been identified, including p38, c-Jun kinase (JNK), and extracellular signal-regulated protein kinase (p42/44 ERK). Typically, growth factors activate the p42/44 MAPK pathway through the sequential activation of the small GTPase Ras, the kinase Raf (an MAPK kinase kinase), and the tyrosine-threonine kinase MEK (an MAPK kinase). Cytokines and stress activate JNK through the small GTPase Rac, the kinase MEKK (an MAPKKK), and the tyrosine-threonine kinases MKK4 and 7 (also known as JNKKs or SEKs). p38 is phosphorylated on tyrosine and threonine residues by MKK3 and 6 and in turn phosphorylates and activates the transcription factor ATF2, MEF2C, and the kinases MAPKAP2/3, resulting in regulation of target gene transcription.11 12 13 The identity of the small GTPase and the MAPKKK involved in the p38 kinase cascade is unclear.
Previous studies have shown that IL-1ß can regulate gene expression
in cardiac myocytes.10 14 15 16 Typically, IL-1ß
activates transcription factors such as nuclear factor 
B and
AP-1, which are involved in induction of inflammatory response
genes.10 17 Comparison of the proximal hBNP promoter with
consensus elements corresponding to known regulatory motifs has
identified potential cis elements, including M-CAT (at
positions -124 and -97), and GATA-4 (-85). These elements are
important in basal, tissue-specific, and inducible regulation of
cardiac genes.18 19 20 In this study, we examined
whether IL-1ß is a direct transcriptional regulator of the hBNP
promoter, whether proximal promoter cis elements are targets
for its action, and whether the p38 kinase or other MAPK signaling
pathways are involved.
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Methods |
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Cell Culture
Ventricular myocyte–enriched cultures were generated from 1- to 2-day-old Sprague-Dawley rat pups (Charles River Laboratories, Kalamazoo, Mich), as described previously,21 according to a protocol approved by the Henry Ford Hospital Committee for Care and Use of Experimental Animals. Ventricular myocytes were cultured in DMEM (Gibco) containing 100 U/mL penicillin, 100 µg/mL streptomycin, 2 mmol/L glutamine, 0.1 mmol/L bromodeoxyuridine, and 10% fetal bovine serum (HyClone) for 40 hours, after which the cells were maintained in serum-free conditions (DMEM plus antibiotics, glutamine, insulin, transferrin, and selenium). After 24 hours, cells were treated with IL-1ß. In selected experiments, pharmacological inhibitors (SB203580, a p38 kinase inhibitor [SB]; PD98059, an MEK inhibitor [PD], and actinomycin D [ActD]) were added 1 hour before IL-1ß, after which the cells were allowed to incubate with the inhibitor plus IL-1ß for 24 hours. The specificity of SB for p38 kinase has been tested in in vitro kinase assays. It has minimal effects on p42/44 MAPK while inhibiting some JNK isoforms at 10-fold higher concentrations than required for inhibition of p38.22
Transfection and Luciferase Assay
Transfection and luciferase activity were assayed as
described previously.21 For the full-length and mutant
hBNP-luciferase (hBNPLuc) constructs, 1 µg was transfected by
electroporation per 3x106 cells. For the
cotransfection studies, 0.5 µg of constitutively active Rac and MKK6
(or its control) and 10 µg of the dominant-negative (dn) mutants
(dnp38, dnRas, dnRaf, dnRac, dnJNKK, or a control expression
vector) were cotransfected with -1818hBNPLuc. These concentrations
were determined in preliminary dose-response studies. After
transfection, the cells were divided into aliquots in 3 wells of a
12-well plate (0.5x106 cells per well;
3x106 cells are originally electroporated, but
50% of the cells die in the process). At 40 hours after
transfection, the medium was changed to serum-free DMEM. The next day,
cells were treated with inhibitors and then IL-1ß. Cells
were harvested 24 hours later, lysed, and assayed for luciferase
activity (Luciferase Assay System, Promega) with an OptoComp 1
luminometer (MGM) according to the manufacturer's protocol. Duplicate
aliquots of cell lysate from triplicate wells were assayed and
averaged. Luciferase activity was normalized to protein levels. Data
were expressed as the mean±SE and analyzed either by
Student's t test or by 1-way ANOVA with multiple pairwise
comparisons made by the Student-Newman-Keuls method. P<0.05
was considered significant.
Plasmid Constructions
Chimeric hBNP-luciferase reporter gene constructs have been
described previously.21 A 3-step polymerase chain reaction
(PCR) protocol was used to generate mutations in the hBNP promoter. For
each cis element, mutant sense and antisense primers were
designed that overlapped the 1 to 3 bp to be mutated. Mutations were
generated on each strand of the hBNP promoter template in 2 separate
PCR reactions (a wild-type sense and mutant antisense primer pair and a
mutant sense and wild-type antisense primer set). The 2 mutant PCR
products were annealed together, and then wild-type primers were
used to amplify the entire region of the proximal promoter. This
procedure resulted in the following mutations: -124 M-CAT (M124;
CATTCCC
GGTACCC); -97 M-CAT (M97; CGGAATGCTTAGTG); and -85 GATA
(mGATA; TGATAATGGTAA). The final PCR products were digested with
appropriate restriction enzymes to isolate the mutated fragments, which
were then subcloned into -1818hBNPLuc. All constructs were verified by
DNA sequencing.
Expression vectors encoding the dominant-negative mutants of Ras (Ras
N17), Raf (Raf 301), and JNKK (K116R) were obtained from Dr Michael
Karin (University of California at San Diego). Dominant-negative
Rac (N17rac2) and constitutively active Rac (V12rac2) and RhoA
(L63rhoA) were obtained from Dr Melanie Cobb (University of Texas
Southwestern). Dominant-negative p38 (KM) and constitutively active
MKK6 [MKK6b(E)] were provided by Dr J. Han (Scripps Institute).
Supplies and Chemicals
IL-1ß was obtained from Sigma Chemical Co. PD, ActD, and SB
were purchased from Calbiochem. Routine laboratory supplies and
chemicals were obtained from Fisher and Sigma.
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Results |
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IL-1ß Stimulates the hBNP Promoter
To test whether IL-1ß activates the hBNP promoter in a dose-dependent fashion, we treated transfected cells with 0.05 to 5 ng/mL IL-1ß for 24 hours. As shown in Figure 1A
, 0.05 to 5 ng/mL IL-1ß
activated the hBNP promoter. Because 5 ng/mL IL-1ß resulted
in maximum activation, this dose was used in subsequent
experiments.
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To examine whether the effect of IL-1ß is the result of a
transcriptional mechanism, transfected cells were pretreated with the
transcriptional inhibitor ActD before treatment with
IL-1ß. Figure 1B
shows that ActD had no effect on basal hBNP
promoter activity but totally inhibited IL-1ß–stimulated activity.
IL-1ß treatment for 3 to 6 hours also stimulated
endogenous rat BNP mRNA (data not shown). These data
implicate a transcriptional mechanism in IL-1ß stimulation of hBNP
promoter activity.
p38 kinase, Rac, and Ras Are Involved in IL-1ß Regulation of the
hBNP Promoter
To investigate whether the p38 kinase pathway is involved in
IL-1ß–stimulated hBNP promoter activity, transfected myocytes were
pretreated with the p38-specific inhibitor SB 1 hour before
administration of IL-1ß. As shown in Figure 2A, SB reduced IL-1ß stimulation of the
hBNP promoter by 50% (P<0.05; n=4). To verify this result,
we used an alternative approach: cotransfection of a dominant-negative
(dn) p38 kinase expression vector. Expression of dnp38 also decreased
IL-1ß–stimulated hBNP promoter activity by 50% (P<0.01;
n=6; Figure 2B). It is possible that SB and dnp38 have different
specificities for the p38 isoforms in cardiac myocytes. Thus we tested
them in combination and found that IL-1ß–stimulated hBNP promoter
activity was reduced by 88% (control, 1; SB+dnp38, 0.7±0.3-fold;
IL-1ß, 4.3±0.6-fold; SB+dnp38+IL-1ß, 1.4±0.7-fold; n=3). Thus
activation of p38 kinase partially mediates the effect of IL-1ß on
the hBNP promoter.
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If IL-1ß signal transduction involves the p38 pathway, then the
effect of IL-1ß should be mimicked by overexpression of the upstream
activator of p38, MKK6. Constitutively active MKK6
[MKK6b(E)] potently stimulated hBNP promoter activity compared with
the 4-fold increase stimulated by IL-1ß (Figure 2C). Addition
of IL-1ß failed to increase MKK6-stimulated activity further,
suggesting that p38 kinase is maximally activated. We verified
that MKK6 stimulation of the hBNP promoter was mediated by p38 kinase
by addition of SB, which decreased hBNP promoter activity by 86%
(Figure 2D).
It is not clear how binding of IL-1ß to its receptor is coupled
to activation of the p38 MAPK signaling pathway. We tested the ability
of small GTPases of the Ras family (Ras, Rac, and Rho) to either
activate the hBNP promoter or inhibit IL-1ß–stimulated
activity. When we cotransfected –1818hBNPLuc with dominant-negative
mutants of Ras and Rac, IL-1ß–stimulated luciferase activity was
decreased by 65% and 90%, respectively (Figure 3A). Overexpression of constitutively
active Rac increased hBNP-luciferase activity 5-fold, and IL-1ß
increased this effect to 8-fold (Figure 3B). The effect of Rac
overexpression was specific, since constitutively active RhoA had no
effect on hBNP promoter activity (data not shown). However, Rac
activation of the hBNP promoter may not involve p38 kinase, as SB was
unable to inhibit this effect (Figure 3B). These data suggest
that signaling pathways downstream from activated Ras and Rac
are involved in IL-1ß regulation of the hBNP promoter.
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Involvement of p42/44 MAPK and JNK
Scherle et al23 report that IL-1ß
activates all three MAPKs (p42/44 ERK, JNK, and p38) in rabbit
articular chondrocytes, whereas other studies report that IL-1ß
selectively activates MAPKs.8 9 10 24 To test
whether p42/44 MAPK is involved in IL-1ß stimulation of the hBNP
promoter, we used a specific inhibitor, PD, which inhibits
MEK, the upstream activator of p42/44 MAPK. Figure 4A shows that PD failed to inhibit the
effect of IL-1ß. In fact, PD by itself increased hBNP promoter
activity in –1818hBNPLuc-transfected myocytes and enhanced the effect
of IL-1ß. This effect of PD was also observed in separate experiments
examining endothelin-1 regulation of the hBNP promoter (data not
shown). Because the effect of PD was contrary to our expectations, we
used a second approach to inhibit the p42/44 MAPK signaling pathway,
overexpression of dominant-negative Raf, the MAPK kinase kinase
associated with activation of MEK and thus p42/44. As shown in Figure 4B, dnRaf had no effect on either basal or IL-1ß–induced hBNP
promoter activity. These data suggest that Ras and Rac activation of
the hBNP promoter involves a mechanism(s) independent of p42/44.
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Because Ras activates Rac in some types of
cells25 and Rac is involved in activation of the JNK
pathway,11 12 we next tested whether IL-1ß stimulation
of the hBNP promoter involves JNK. To do this we used a
dominant-negative mutant of JNKK, an upstream activator of
JNK. Figure 4C shows that dnJNKK had no effect on
IL-1ß–stimulated hBNP promoter activity in transfected cardiac
myocytes. We also cotransfected a JNKK expression vector with the hBNP
promoter and then stimulated the myocytes with IL-1ß, but
activated JNKK had no effect on the hBNP promoter (data not
shown), confirming the results of the dnJNKK experiments. These data
suggest that Ras and Rac activation of the hBNP promoter involves a
mechanism(s) independent of JNK, although they do not exclude the
involvement of JNK isoforms insensitive to dnJNKK.
IL-1ß Regulation of the hBNP Promoter Targets the Proximal
M-CAT Element
The proximal hBNP promoter contains cis elements
involved in tissue-specific expression in cardiac myocytes, including
GATA-4 (-85) and M-CAT (-124 and -97) (Q.H., G.W., M.L., unpublished
observations, 1998). To investigate whether these elements are
involved in IL-1ß regulation of the hBNP promoter, we mutated each of
them and transfected these mutated constructions into myocytes.
Mutation of the M-CAT element at –97 reduced IL-1ß stimulation of
the hBNP promoter by 60%; however, there was no effect of mutation of
the other elements (Figure 5A). To
test whether p38 kinase targets the M-CAT element at position
-97, we cotransfected 1818(M97)hBNPLuc with the MKK6 expression
vector. MKK6 activation of the mutated hBNP promoter was decreased 35%
relative to the wild-type promoter (Figure 5B). Thus a target
for p38 kinase regulation of the hBNP promoter is the M-CAT
element.
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Discussion |
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Our data are the first to demonstrate that IL-1ß regulates the hBNP promoter through a transcriptional mechanism targeting the proximal M-CAT element and that the effect of IL-1ß is mediated by Ras-, Rac-, and p38-dependent pathways. Moreover, the M-CAT element is a target for the p38 kinase signaling pathway in cardiac myocytes.
IL-1ß signal transduction is complex and can include activation
of JNK, p42/44, and p38 kinases in different types of
cells.8 9 10 23 24 Activation of p38 kinase can have
opposite effects on IL-1ß–stimulated genes in the same cell
type8 or regulate some (but not all) responses to
IL-1ß.9 Our data using both pharmacological and
molecular approaches indicate that p38 kinase is involved in IL-1ß
regulation of the hBNP promoter, a result not reported previously to
our knowledge. In cardiac myocytes, IL-1ß regulation of the adhesion
proteins ICAM and VCAM also involves p38 kinase,10 as does
IL-1ß regulation of inducible nitric oxide synthase and
cyclooxygenase-2 (M.L., unpublished observations,
1998). Moreover, our studies using SB and the p38 kinase
activator MKK6 support the data of Zechner et
al,26 who showed that MKK6 activates the rat ANP
and BNP promoters and that SB inhibits this effect by 70%. They also
showed that the 
-adrenergic agonist phenylephrine (PE)
stimulated the rat ANP and BNP promoters through a p38
kinase–dependent pathway and that SB inhibited PE stimulation of the
rat BNP promoter by only 40%, similar to our results.
Our data indicate that IL-1ß signaling in cardiac myocytes involves the small GTPases Ras and Rac but not Rho. Ras activates the p42/44 pathway and Rac the JNK pathway in cardiac myocytes,26 but neither pathway seems critical for IL-1ß regulation of the hBNP promoter in myocytes. Similarly, neither pathway is involved in PE stimulation of the rat ANP and BNP promoters.26 27 28 Additionally, we found that the MEK inhibitor PD activated the hBNP promoter and potentiated the effect of IL-1ß, suggesting that either MEK itself or p42/44 negatively regulates the promoter, as shown for PE regulation of the rat ANP promoter.27 29
How Ras and Rac couple IL-1ß binding to its receptor with activation of downstream signaling pathways is unclear. In preliminary studies, we have found that a dominant-negative mutant of the nonreceptor tyrosine kinase Src inhibits IL-1ß stimulation of the hBNP promoter by 50% (Q.H., M.L., unpublished data, 1998), suggesting that Src may transmit signals from the IL-1ß receptor to downstream effectors, including p38 kinase. Based on our preliminary pharmacological data, other kinases may also be involved, including protein kinase C (PKC) and phosphatidylinositol-3-kinase (PI3K).
An intriguing result of our study is that IL-1ß stimulation of
the hBNP promoter is Rac-dependent but that Rac activation of the
promoter is not p38 kinase–dependent. This suggests that other
Rac-mediated signals, such as reactive oxygen species,30
may be involved in IL-1ß stimulation of the hBNP promoter.
Alternately, Rac may activate a form of p38 kinase not
inhibited by SB, such as p38
(also called SAPK3 or
ERK6)31 or p38
.32 Because MKK6
activates both of these novel p38 kinases whereas SB does not
inhibit them,31 32 this could explain why SB only inhibits
MKK6 activation of the hBNP promoter by 86% (Figure 2D).
We have shown previously that the full-length hBNP promoter is more active in myocytes than in fibroblasts and that a region in the proximal promoter located between -127 and -40 consists of potential cis elements arranged in tandem: M-CAT (-124 and –97) and GATA (-85), which are critical for cardiac-specific expression (Reference 2121 ; Q.H., M.L., unpublished data, 1998). The present study indicates that inducible regulation of the hBNP promoter also targets the proximal promoter region, in particular the M-CAT element at -97. We believe this effect is specific for IL-1ß, since the hypertrophic growth factor endothelin-1 did not target this region (Q.H., M.L., unpublished observations, 1998). Our data would also suggest that IL-1ß targets the M-CAT element through a p38 kinase–dependent pathway. A similar mechanism may be involved in PE regulation of the rat BNP promoter. Thuerauf and Glembotski33 have shown that PE regulation of the rat BNP promoter targets a proximal M-CAT element and that this effect is Ras- and PKC-dependent. The same group has also shown that PE regulation of the rat BNP promoter involves p38 kinase.26 Thus it is interesting to speculate that p38 may target either (1) a protein binding to the M-CAT element, (2) a protein binding to an adjacent site, or (3) another kinase or phosphatase, which in turn targets the element. This would represent an important, novel action of p38 kinase. Previous studies have implicated p38 in the activation of other transcription factors, including ATF2, ELK1, MEF2C, and ATF611 12 13 34 ; whether these elements also participate in the regulation of the hBNP promoter is unknown.
In summary, our results demonstrate that IL-1ß regulation of the hBNP promoter is Ras-, Rac-, and p38-dependent and that p38 kinase may target the proximal M-CAT element. Since BNP synthesis is induced in the infarcted myocardium and is high in the failing heart, and plasma BNP level is a marker of left ventricular dysfunction, elucidation of the complex molecular signals that regulate its synthesis may lead to understanding how ischemic injury progresses into heart failure.
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL03188 and HL28982 (Dr LaPointe). We thank Drs Michael Karin, Melanie Cobb, and J. Han for providing reagents. We also thank Fangfei Wang and Mary Dowd for their excellent technical assistance.
Received September 15, 1998; first decision October 14, 1998; accepted October 23, 1998.
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