(Circulation. 1995;92:1866-1875.)
© 1995 American Heart Association, Inc.
Articles |
Induction of Interleukin-6 Synthesis in the Myocardium
Potential Role in Postreperfusion Inflammatory Injury
From the Section of Cardiovascular Sciences, The Methodist Hospital, The DeBakey Heart Center and Department of Medicine, Houston, Tex (G.L.K., K.A.Y., L.H.M., M.L.E.); the Speros P. Martel Section of Leukocyte Biology, Department of Pediatrics and Texas Children's Hospital, Houston, Tex (G.L.K., C.W.S.); and Discovery Research, Upjohn Laboratories, Kalamazoo, Mich (A.M.M.).
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Abstract |
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Background Neutrophil-induced injury of myocardial cells requires the expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte surface and is mediated by ICAM-1–CD11b/CD18 adhesion. We have previously shown that interleukin-6 (IL-6) cytokine activity, present in cardiac lymph, induces ICAM-1 on isolated cardiac myocytes. Furthermore, in previous in vivo studies, we have also shown ICAM-1 mRNA induction in the myocardium within the first hour of reperfusion in the previously ischemic viable zone. We hypothesized that induction of IL-6 synthesis in the myocardium was an integral part of the reaction to injury resulting from ischemia and reperfusion and was associated with induction of ICAM-1 on myocardial cells.
Methods and Results In this study, cloned canine IL-6 cDNA was used as a molecular probe to study the regulation of IL-6 in an awake canine model of myocardial ischemia and reperfusion. IL-6 mRNA was induced in ischemic and reperfused segments of myocardium preferentially in segments previously exposed to severe ischemia. Peak levels of IL-6 mRNA were reached within 3 hours of reperfusion. At the same time, IL-6 mRNA and ICAM-1 mRNA were found in the same myocardial segments. In contrast to hearts that were ischemic for 1 hour and reperfused for 3 hours, nonreperfused hearts after 4 hours of persistent ischemia demonstrated minimal induction of ICAM-1 or IL-6 despite similar degrees of injury and blood flow reductions during ischemia. After 24 hours of persistent ischemia, levels of IL-6 mRNA were comparable to those observed in hearts that were ischemic for 1 hour and subsequently reperfused for 24 hours.
Conclusions Our results demonstrate induction of IL-6 mRNA in the myocardium and that this synthesis is accelerated by reperfusion. Evidence is also provided to show that peak IL-6 mRNA precedes that of ICAM-1 mRNA. These findings are compatible with our hypothesis that IL-6 is important in the induction of ICAM-1 in the area of ischemia. In addition, these studies suggest that the necessary factors to promote adhesive interactions between transmigrated neutrophils and cardiac myocytes are present in reperfused myocardium.
Key Words: reperfusion • myocardial infarction • interleukin • blood cells
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Introduction |
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Although the association of inflammation with acute myocardial infarction has been described for more than a century,1 its role in injury extension has only recently been proposed.2 The principal focus of this recent interest has related to the potential role of neutrophil infiltration in postreperfusion injury.3 Our laboratory has studied neutrophil-induced injury of isolated adult canine cardiac myocytes as a potential mechanism of inflammation-induced reperfusion injury. Neutrophils adhere to viable cardiac myocytes only when the neutrophil is stimulated with a chemotactic agent and the myocyte has been incubated with a cytokine.4 Neutrophil adhesion to cardiac myocytes is dependent on CD18 integrin activation and also on the induction of ICAM-1 on cardiac myocytes.4 5 Subsequent experiments showed that neutrophil adhesion to cardiac myocytes resulted in lethal myocyte injury mediated by a transfer of reactive oxygen that was dependent on CD11b/CD18–ICAM-1 adhesion.6
The pertinence of these in vitro studies to reperfusion-associated inflammatory injury in a model of canine myocardial ischemia and reperfusion has been suggested by another line of investigation. In an awake canine model with a permanently cannulated cardiac lymph duct, we demonstrated the presence in postischemic cardiac lymph of chemotactic factors that are neutralized by a C5a antibody7 8 and cytokine activity capable of stimulating ICAM-1 expression on isolated cardiac myocytes.9 10 In these latter experiments, stimulation of myocyte ICAM-1 induction by cardiac lymph was neutralized by a polyclonal antibody to human IL-6.9 These associations led to more direct experiments on ischemic and reperfused myocardial tissue that demonstrated induction of ICAM-1 in vivo.10 More recently, we used in situ hybridization techniques to demonstrate that the induction of ICAM-1 mRNA in jeopardized viable myocardium occurs where maximal inflammatory infiltrate is seen.11 This creates a potential interface between activated neutrophils and myocardial cells, induced to express ICAM-1, that might lead to the inflammatory injury we demonstrated in vitro.4 5 6 The hypothesis of this study was that induction of IL-6 synthesis was an integral part of the reaction to injury resulting from ischemia and reperfusion and was associated with induction of ICAM-1 on myocardial cells. Since the role of myocyte ICAM-1 in neutrophil-induced injury may also be important pathologically, the present study seeks to investigate the mechanism of ICAM-1 induction and examine the correspondence of our in vitro studies with conditions observed after ischemia and reperfusion. This study demonstrates the induction of the IL-6 gene in ischemic and reperfused myocardium. In keeping with our previous observations in cardiac lymph,9 the induction of myocardial IL-6 occurs very rapidly upon reperfusion. Furthermore, this induction is seen only in segments that are severely ischemic. Finally, the relation of IL-6 to ICAM-1 induction is further suggested by the concordance of ICAM-1 mRNA and IL-6 mRNA in the same ischemic and reperfused myocardial segments.
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Methods |
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Molecular Cloning
A specific canine IL-6 probe was initially prepared by reverse transcription PCR using RNA extracted from LPS-stimulated peripheral blood mononuclear cells. Cells were isolated from citrate-anticoagulated venous blood by dextran sedimentation and Ficoll-Hypaque gradient centrifugation. The banded mononuclear cells were resuspended in RPMI 1640 with 10% FCS. Cells were then stimulated with LPS (Sigma Chemical Co) 100 µg/mL for 4 hours at 37°C. Total RNA was isolated at the end of the 4-hour incubation period with a modification of the acid-guanidinium-thiocyanate-phenol-chloroform extraction method12 and resuspended in diethyl pyrocarbonate–treated water. Reverse transcription protocols were performed with 3 µg of total RNA in each sample. After first-strand synthesis, primed with oligo-dT, aliquots of the reverse transcription reaction were amplified with the following primers: 5' primer, 5'-GATCGGATCCGCTATGAACTCCCTCTCC-3', 3' primer, 5'-GATCAAGCTTAGGTTTCTGACCAGA-3' at a final concentration of 0.025 µmol/L. The nucleotide sequence of the primers was based on a highly conserved sequence of human and porcine IL-6 cDNA13 14 and corresponded to base pairs 30 through 48 and 715 through 729 of the human IL-6 cDNA.13 PCR was performed with 5 U Taq DNA polymerase (Promega Corp) for 25 cycles of 93°C, 1 minute; 60°C, 30 seconds; and 72°C, 30 seconds. The final product was purified, cloned into the BamHI and HindIII restriction endonuclease sites of M13mp19,15 and sequenced on an Applied Biosystems model 373A automated DNA sequencer. Samples were sequenced with Taq DNA polymerase and fluorescently labeled M13 universal and reverse sequencing primers. This PCR product was used to screen two cDNA libraries prepared from LPS or TNF-
–stimulated CJVECs in the 
ZAP II vector (Stratagene
Cloning Systems). The first cDNA library screened was stimulated with
LPS and used an oligonucleotide encoding oligo-dT
(13 mer) and a Xho I restriction endonuclease recognition
site to prime the first-strand cDNA synthesis. The PCR product
was labeled with 32P by
random-hexanucleotide priming16 and
was used to screen 1x106 plaques. Screening was
performed by plaque filter hybridization methods on duplicate
filters.17 Filters were hybridized in rapid hybridization
buffer (Amersham Corp) at 65°C for 2 hours and then washed with 1x
SSPE/0.5% SDS at 65°C for 20 minutes followed by 0.5x SSPE/0.5%
SDS for 20 minutes. Hybridizing clones were plaque-purified in
subsequent rounds of screening and rescued in pBluescript SK(-)
(Stratagene Cloning Systems) by the in vivo excision method. The
complete nucleotide sequence of both strands of the longest
clone (dIL-6-1) was determined on an Applied Biosystems model 373A
automated sequencer. Since clone dIL-6-1 did not encode an initiation
codon and its 5' end began at the equivalent of residue 14 of the human
IL-6 protein, a second cDNA library was screened. This second library
used a random-hexamer oligonucleotide strategy to
prime the first-strand cDNA synthesis and was made from
TNF-–stimulated (30 U/mL; 3 hours, 37°C) CJVEC poly (A+)
RNA.
Approximately 5x105 plaques from this library were
screened with a 150-bp probe derived by Rsa I restriction
endonuclease digestion of a fragment corresponding to the 5' end of
dIL-6-1. Screening was performed under the same conditions as used to
screen the oligo-dT–primed cDNA library. Four clones were
isolated with this probe. These clones were plaque-purified before
plasmid rescue in pBluescript SK(-). The 5' and 3' ends of
all four
clones were sequenced on an Applied Biosystems model 373A automated DNA
sequencer by the dideoxynucleotide termination
method18 and fluorescently labeled reverse and
universal sequencing primers. All four clones contained the initiation
codon and extended into the 5' untranslated region. The complete
nucleotide sequence of both strands of clone dIL-6-8 was
completed by primer walking. DNA sequences were analyzed by the
suite of programs within EUGENE and SAM, as
supported by the Molecular Biology Information Resource, Baylor College
of Medicine, Houston, Tex.
Ischemia-Reperfusion Protocols
Healthy mongrel dogs (15 to 25
kg) of either sex were surgically
instrumented as previously described.10
Anesthesia was induced with methohexital sodium 10 mg/kg IV
(Brevital; Eli Lilly and Co) and maintained with the inhalational
anesthetic isoflurane (Anaquest). A midline thoracotomy provided access
to the heart and mediastinum, and cannulation of the cardiac lymph duct
was then performed as previously described.10
Subsequently, a hydraulically activated occluding device and a
Doppler flow probe7 10 were secured around the
circumflex coronary artery just proximal or just distal to the
first branch. Choice of location depended on the proximity and anatomic
arrangement of lymphatic vessels so that subsequent dissection would
not damage the lymphatic system. In animals selected for experimental
assessment of cardiac lymph, intact lymphatic vessels draining the
regions of ischemic myocardium were identified by
Evans blue dye (0.05 mL) injected into the free wall of the left
ventricle after the occluder and flow probe were in place. The
appearance of Evans blue dye in the cardiac lymph cannula confirmed the
patency of the lymph vessels. Indwelling cannulas placed in the right
atrium, left atrium, and femoral artery allowed blood sampling and
pressure monitoring as needed. The animals were allowed to recover for
72 hours before occlusion. Ischemia-reperfusion protocols
were performed in awake animals as described.10 The
coronary artery was occluded by inflating the coronary
cuff occluder until mean flow in the coronary vessel was zero,
as determined by the Doppler flow probe. After 50 minutes of
occlusion, radiolabeled microspheres (for subsequent blood flow
determinations) were injected into the left atrium. For most
experiments (total of 22, see below), at the end of 1 hour the cuff was
deflated and the myocardium was reperfused. Reperfusion
intervals ranged from 1 to 24 hours. In 8 experiments, reperfusion was
not instituted. In 4 of these 8, the period of ischemia was
extended to 4 hours, and in the remaining 4, it was extended to 24
hours. Circumflex blood flow, arterial blood pressure,
heart rate, and ECG (standard limb II) were recorded continuously.
Analgesia was achieved with pentazocine (Talwin; Winthrop
Pharmaceuticals) 0.1 to 0.2 mg/kg IV. Lymph samples were collected from
the cannulas in tubes containing 10 U preservative-free heparin.
The samples were spun in a tabletop centrifuge at
13 000g for 5 minutes. Aliquots of supernatants were
immediately frozen in liquid nitrogen and stored at -80°C until
ready to use. For all incubation protocols, lymph samples, once thawed,
were used immediately. After the reperfusion periods, hearts were
stopped by the infusion of saturated potassium chloride, removed from
the chest, and sectioned from apex to base into four transverse rings
l cm thick. The posterior papillary muscle and the posterior free
wall were identified. Transmural myocardial samples (1.0 g) were
isolated from myocardial rings and labeled as control (obtained from
the anterior wall) or infarcted (obtained from the posterior papillary
muscle and posterior free wall) on the basis of anatomic location
within the distribution of the circumflex artery and visual inspection.
Myocardial samples were then minced into smaller pieces: first a
transmural section was taken from the middle of the sample and fixed in
10% buffered formalin for histological studies, then
the top and bottom halves were minced into smaller pieces and divided
into two halves. The first half was used for blood flow determinations
with radiolabeled microspheres as previously
described.10 19 20 The remaining portions
of each sample
were immediately frozen in liquid nitrogen. Frozen tissue samples were
homogenized and processed for RNA studies. Analyses
of RNA, blood flow determinations, and histopathological examinations
of samples obtained from each experiment were conducted independently
(in separate laboratories) and in a blinded fashion. Once the
independent analyses of the data were completed, the
information was gathered and a final analysis performed. The
first step in this final analysis was to determine the presence
or absence of a myocardial infarct in each separate experiment. The
presence of a myocardial infarct was based on light-microscopic
examination of hematoxylin-eosin–stained tissue sections.
Basic fuchsin staining (Titus Lie stain) was also used to aid in the
identification of an infarct.10 11 The presence of a
myocardial infarct in experiments with short reperfusion intervals (in
which myocardial necrosis is not easily discernible) was defined in
hematoxylin-eosin–stained tissue sections by findings of
contraction bands, increased eosinophilia, "wavy fibers,"
interstitial edema, and infiltration of neutrophils, all in
segments displaying markedly reduced blood flow during the
ischemic period. For experiments lasting 24 hours after the
start of the ischemic insult, the presence of
histological elements characteristic of myocyte
necrosis was added to the required criteria. A subsequent step in the
final analysis of each sample was to correlate the level of
IL-6 mRNA with the blood flow quantified by microspheres. This
final analysis allowed for the classification of myocardial
segments into two groups: control (no evidence of necrosis, normal
blood flow) and ischemically injured myocardium (by
methods mentioned above and reductions in blood flow). The data in this
article describe the findings in these two groups of segments. Segments
that were initially identified as infarcted in our initial blind
assessment but had normal blood flow during occlusion did not have
detectable levels of IL-6 or ICAM-1 mRNA and therefore were analogous
to control segments (data not shown).
Data for ischemia-reperfusion studies were derived from 22 experiments. For all 22 experiments, the circumflex artery was occluded for 1 hour, and subsequently the myocardium was reperfused for 1 (7 experiments), 3 (8 experiments), or 24 (7 experiments) hours. In 8 additional experiments, the myocardium was rendered ischemic and reperfusion was not instituted. In 4 of these experiments, the myocardium remained ischemic for 4 hours, and in the other 4, the period of persistent ischemia was extended to 24 hours. To examine the relation of IL-6 induction to reperfusion, levels of IL-6 mRNA in ischemic and reperfused myocardial segments were compared directly with the levels found in persistently ischemic segments. All animal protocols were approved by the appropriate institutional review committee and conformed to institutional guidelines.
Isolation and Culture of CJVECs
Cells were obtained by
modification of the method of
Ford.21 Jugular veins were everted on glass rods and
incubated in collagenase solution (Boehringer
Mannheim type A) for 20 minutes. Cells were collected by
centrifugation and suspended in DMEM containing 5%
FCS, 5% bovine calf serum, 50 µg/mL endothelial cell
growth factor (Collaborative Research), 50 U/mL heparin, 1 mmol/L
sodium pyruvate, and antibiotics. Cells were seeded in Primaria flasks
(Becton Dickinson). After 2 to 4 days of incubation at 37°C in a
CO2 incubator, areas of cells with "cobblestone"
morphology were collected by scraping, transferred to
gelatin-coated flasks (0.1%, Difco), and grown to confluence. For
incubation experiments with cardiac lymph, aliquots of lymph obtained
before coronary occlusion and at designated times during
reperfusion were diluted 1:7 and incubated with CJVEC monolayers for 2
hours at 37°C. Cells were then lysed, and RNA was isolated.
RNA Isolation and Northern Blot Analysis
RNA was isolated
from myocardial tissue segments or cultured
CJVECs by the
acid-guanidinium-thiocyanate-phenol-chloroform
procedure.12 RNA (5 to 20 µg) was electrophoresed in 1%
agarose gels containing formaldehyde, then transferred to a nylon
membrane (Gene Screen Plus; New England Nuclear) by standard
procedures.17 Loading of RNA was monitored with ethidium
bromide staining as well as by probing of the nylon membranes with
human GAPDH. Membranes were hybridized in QuikHyb hybridization buffer
(Stratagene Cloning Systems) at 68°C for 2 hours with
1x106 cpm/mL random-hexamer
32P-labeled canine ICAM-1 or IL-6 cDNA
probe.10 16 Canine ICAM-1 cDNA probe was prepared as
previously described,10 and the canine IL-6 cDNA probe was
generated by BstXI and Ssp I restriction
endonuclease digestion of clone dIL-6-1. This cDNA fragment was 415 bp
long and did not include any nucleotide sequences from
pBluescript SK(-) or the poly (A) tail. For certain experiments, the
same membrane was probed with more than one cDNA. In these experiments,
each probe was stripped from the membrane before subsequent
hybridizations. Filters were washed with 2xSSPE at 68°C for 20
minutes, with 1xSSPE/1% SDS at 68°C for 15 minutes, and with
1xSSPE at 21°C for 15 minutes and were then exposed to Hyperfilm-MP
(Amersham) for 24 to 96 hours. Analyses of radioactivity were
performed on a Betascope 603 blot analyzer (Betagen).
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Results |
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Molecular Cloning of Canine IL-6
An LPS-stimulated, oligo-dT–primed, CJVEC cDNA library was screened with a specific canine IL-6 PCR probe encoding the equivalent of nucleotides 30 to 729 of the human IL-6 cDNA.13 This probe was generated by use of oligonucleotides encompassing highly conserved sequences of human and porcine IL-6 as primers for the amplification reaction.13 14 Thirty-four
cDNA clones
hybridized
and contained inserts of 400 bp to 1 kb that upon Southern blotting
demonstrated strong hybridization signals. Clone dIL-6-1, the largest
of these clones, contained an insert 1034 bp in length. However, clone
dIL-6-1 did not encode an initiation codon and extended from the
equivalent of residue 14 of the human IL-6 primary protein to the poly
(A) tail. In an attempt to isolate a clone encoding the remaining 5'
sequences of the IL-6 cDNA, we screened a random-primed cDNA
library with a probe representing the 5' end of clone
dIL-6-1. This library was prepared from TNF-–stimulated
endothelial cell poly (A+) RNA and was screened under
the same conditions as the oligo-dT–primed library. Four
clones were isolated and subjected to further analyses. All
four clones encoded the remainder of the IL-6 signal peptide, contained
the initiation codon, and extended into the 5' untranslated region. One
of these clones, dIL-6-8, was sequenced in its entirety.
Nucleotide sequences derived from clones dIL-6-1 and
dIL-6-8 were used to compile the complete canine IL-6 cDNA (Fig
1
). The nucleotide sequences of the 5'
untranslated region, along with the first four codons and the first
nucleotide of the fifth codon derived from dIL-6-8, were
added to those of clone pdIL-6-1 to construct the complete canine IL-6
cDNA. DNA sequence and restriction endonuclease analysis
established the relation of each of these cDNA clones (Fig 2).
Sequence analysis revealed that the canine
IL-6 cDNA is 1104 bp in length, consisting of a
57-nucleotide-long 5' untranslated region followed by a
single open-reading frame of 621 bp and a 3' untranslated region of
426 bp excluding the poly (A) tail. The open-reading frame begins
with the AUG start codon at position 58 and ends with the TAG stop
codon at position 679. The length of the 3' untranslated region of
canine IL-6 is similar to that reported for human, porcine, and mouse
IL-6.13 14 22 Furthermore, an 85%
nucleotide
sequence identity is present between human and canine 3'
untranslated regions (Fig 3). Within the 3' untranslated
region of canine IL-6 are five copies of the pentamer AUUUA found in
many cytokines and chemokines. These sequences are capable of
reducing mRNA stability23 24 and accelerating nuclear
transport.25 Four of these pentamers are completely
conserved in human IL-6 (Fig 3). Finally, a eukaryotic
consensus polyadenylation hexamer, AATAAA, is followed 9 bp downstream
by a poly (A) tail.26
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The complete IL-6 cDNA encodes a
207–amino acid precursor protein. The
nucleotide sequences in the vicinity of the AUG provide the
context for translation initiation and are in agreement with many of
the known consensus sequences present in
eukaryotes.27 28 Furthermore, the canine IL-6
initiation
motif CAGCTAUGA is identical to the human,13
porcine,14 and bovine29 IL-6 homologues.
After the N-terminal methionine, there is a 23–amino acid region
typical of a signal peptide.30 This N-terminal signal
peptide is highly homologous to those of human, porcine, and bovine
IL-6.13 14 29 However, all of the clones
isolated from
both cDNA libraries contained a 15-nucleotide deletion
corresponding to amino acids 8 through 12 of the human IL-6 primary
protein. Interestingly, this region corresponds to the junction of the
first and second exons in the genomic structure of human31
and mouse IL-6.32 Nucleotide deletions in the
IL-6 signal peptide have also been reported for murine and rat IL-6
cDNA.22 33 The canine IL-6 protein deduced from the
cDNA
sequence displayed 60% overall identity to human IL-6. It also
displayed high levels of amino acid homology to porcine IL-6, being
70% identical (Fig 4). In total, 109 amino acids are
identical between the three species, and all four cysteine residues
present in human and porcine IL-6 are conserved. There is also
remarkable similarity with human and porcine IL-6 in terms of the
signal peptide sequence and total length of the
proteins.13 14 Canine IL-6 does not contain potential
N-linked glycosylation sites.
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Regulation of IL-6 Expression in CJVECs
Regulation of IL-6
gene expression was first studied in vitro in
cultured CJVECs. Northern analysis using the canine IL-6 cDNA
as a probe demonstrated that cultured CJVECs were capable of expressing
IL-6 mRNA (Fig 5). The main transcript was identified as
a 1.1-kb hybridizing band. Under the specific culture conditions, we
occasionally detected minimal levels of IL-6 mRNA as a single species
in untreated control samples. Incubation of CJVECs with TNF-
rapidly elicited a marked increase in IL-6 mRNA. Kinetic studies of the
induction of IL-6 mRNA demonstrated peak levels after only 30 minutes
of stimulation. Steady-state levels of IL-6 mRNA remained elevated
for several hours, returning to baseline after 5 hours of stimulation.
These results are consistent with the known induction of IL-6
on human endothelial cells by cytokines in
vitro.34
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Induction of IL-6 mRNA in CJVECs by Postischemic
Cardiac Lymph
Cardiac lymph, representing myocardial extracellular
fluid, was collected via cannulation of the cardiac lymphatic system
and assayed for its ability to induce IL-6 mRNA in CJVECs. As shown in
Fig 6, postreperfusion cardiac lymph elicited IL-6 mRNA
when incubated with CJVECs in all samples tested. In contrast,
preischemic lymph did not elicit significant levels of IL-6
mRNA. Peak stimulatory activity for IL-6 was present in the first
hour after reperfusion of the previously ischemic
myocardium.
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Regulation of IL-6 mRNA in Ischemic and Reperfused
Myocardium
The expression of IL-6 mRNA after experimental circumflex
coronary artery occlusion and reperfusion was assessed in
ischemic and reperfused myocardial segments. These segments
were characterized for their blood flow during occlusion by use of
radiolabeled microspheres. Representative
experiments in animals subjected to 1 hour of coronary
occlusion and 1 hour of reperfusion are shown in Fig 7.
In the experiment illustrated on the right (lanes C through G), the
animal sustained a large myocardial infarction. Significant induction
of IL-6 mRNA was observed in all ischemic and reperfused
myocardial samples analyzed (lanes D through G). IL-6 mRNA was
not detectable in normally perfused anterior ventricular
wall segments (lane C). Contrasting findings were evident in the
experiment illustrated on the left (lanes A and B), which demonstrated
no evidence of significant blood flow reduction after identical
coronary occlusion and reperfusion protocols (lane B). In this
experiment, IL-6 mRNA was not elicited in any of the myocardial tissue
segments analyzed. Similar findings were observed in an
additional series of experiments in which the reperfusion interval was
extended to 3 hours. Highest levels of IL-6 mRNA were observed in the
most ischemic myocardial segments (Fig 8, lanes C and
D). IL-6 mRNA was also detected in segments with more
modest blood flow reductions but was much less intense than observed
with more severe degrees of ischemia. No detectable levels of
IL-6 mRNA were present in normally perfused myocardial segments
(lanes A and B). Coronary occlusions not associated with
significant levels of ischemia, presumably because of
collateral blood flow, did not elicit measurable levels of IL-6 mRNA
despite identical occlusion and reperfusion intervals (Fig 8,
lanes F
and G).
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To directly assess the relation of time on induction of
myocardial IL-6
mRNA, a series of experiments with various intervals of reperfusion
were compared. In all 5 experiments shown in Fig 9, the
circumflex coronary artery was occluded for 1 hour, and
subsequently the myocardium was reperfused for 1, 3, or 24
hours. A time-dependent induction of the IL-6 gene was present
in ischemic and reperfused segments of these 5 animals.
Steady-state levels of IL-6 mRNA peaked 3 hours after reperfusion
and remained elevated for 24 hours after reperfusion. IL-6 mRNA levels
were inversely related to regional blood flow during ischemia,
with the highest levels being detected in the myocardial segments
displaying the greatest degree of ischemia. Concurrent
assessments of ischemic blood flow in 22 experiments with
intervals of reperfusion ranging from 1 to 24 hours demonstrated that
only segments with reductions in blood flow of >50% demonstrated
measurable levels of IL-6 mRNA. Segments with blood flow reductions
>80% generally displayed the highest levels of IL-6 gene induction
compared with less ischemic myocardial segments.
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To examine whether
ICAM-1 mRNA was detectable during early reperfusion,
in the same segments in which IL-6 induction was found, levels of mRNA
for both genes were assessed in the same ischemic and
reperfused myocardial segments. Fig 10 shows
experiments in which the myocardium was ischemic
for 1 hour and subsequently reperfused for 3 hours. Four separate
experiments are shown, each one identified by brackets at the bottom of
Fig 10. Consistent with our previous observations after 3
hours
of reperfusion, ICAM-1 is induced in ischemic and reperfused
segments of myocardium.10 In all 4 experiments
shown, ICAM-1 mRNA was detected in the same ischemic and
reperfused segments in which IL-6 mRNA was found. This finding was
invariably present during the first 3 hours of reperfusion after 1
hour of ischemia.
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Reperfusion Accelerates the Induction of Myocardial IL-6
mRNA
The role of reperfusion in the myocardial induction of IL-6 mRNA
was directly assessed in a subsequent series of experiments comparing
experiments with and without reperfusion (Figs 11 and
12). In contrast
to the high levels of IL-6 mRNA observed in the ischemic and
reperfused myocardium, in nonreperfused segments after 4
hours of persistent ischemia without reperfusion, we detected
only minimal levels of IL-6 mRNA (Fig 11). These
findings were evident in the presence of comparable degrees of
myocardial blood flow reductions. In the absence of reperfusion,
minimal levels of IL-6 mRNA were observed during the first 4 hours of
ischemia in four separate experiments. In these four
experiments, a total of 14 separate segments were examined. Six of the
14 segments studied had relatively low but detectable levels of IL-6
mRNA. No detectable levels of IL-6 mRNA were found in the remaining 8
segments in this series of studies. Furthermore, when the radioactivity
in each of the lanes representing the levels of IL-6 mRNA
in each myocardial segment was quantified, it did not exceed 15% of
equally ischemic but reperfused segments that originated from
six separate experiments that were ischemic for 1 hour and
reperfused for 3 hours (data not shown). As previously shown in Fig
10
,
a consistent finding in this type of experiment was the
induction of ICAM-1 mRNA in the same myocardial segments in which IL-6
mRNA was found. The role of ischemia and reperfusion on ICAM-1
induction has been previously described.10 11
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Contrasting findings were evident in the experiments illustrated in Fig
12. After persistent ischemia for 24 hours,
levels of IL-6 mRNA were present in ischemic segments and
were comparable to those observed in segments that were
ischemic for 1 hour and reperfused for 24 hours (Fig 12).
These
findings are representative of four separate
experiments. In agreement with the experiments in which reperfusion was
instituted, concurrent assessment of myocardial blood flow indicated
that the degree of ischemia was a major determinant regulating
the levels of induction of IL-6 mRNA. Highest levels of induction were
present in segments demonstrating the lowest levels of blood flow,
whereas IL-6 mRNA was not detectable in normally perfused segments.
IL-6 mRNA was detected in ischemic segments with moderately
diminished levels of blood flow but was less than observed with more
severe blood flow reductions.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In this study, we describe for the first time the isolation and characterization of cDNA clones encoding the canine IL-6 gene. We used this cDNA as a molecular probe to investigate the regulation of IL-6 in the context of myocardial ischemia and reperfusion. We have provided direct evidence that IL-6 is rapidly induced in the myocardium after reperfusion of the previously ischemic heart. This report extends our previous observations that postreperfusion cardiac lymph contains cytokine activity.9 This activity is capable of inducing ICAM-1 mRNA expression and ICAM-1–dependent adhesion of neutrophils to cardiac myocytes, both of which are reduced with a polyclonal antibody directed against human IL-6.9 10 It also strengthens our insights into the induction of the ICAM-1 gene in the myocardium10 11 by providing molecular evidence for the induction of a cytokine likely to be a potential stimulus of myocyte ICAM-1 synthesis in vivo.9
On the basis of nucleotide sequence analysis and comparisons of the deduced protein sequence, we established that the cDNA clones isolated contain the complete open-reading frame of the canine homologue of IL-6. The canine IL-6 protein is 70% identical with its corresponding porcine sequence and 60% identical with human IL-6. While the degree of similarity between human and canine IL-6 proteins is surprisingly low, in view of the evidence that recombinant human IL-6 acts on canine cardiac myocytes,9 a similar phenomenon has been observed between human and rat IL-6. Human IL-6 is only 58% identical to rat IL-6, yet human IL-6 acts on rat liver cells, in which it must be recognized by the IL-6 receptor.33 Quite possibly, a receptor binding domain of IL-6 is conserved across these species.33 Such a proposal is further supported by the finding that all cysteine residues present in human IL-6 are conserved in both canine and rat IL-6, predicting the same disulfide bond pattern and perhaps similar tertiary structure.
A striking feature of the IL-6 gene compared across species is the high degree of nucleotide sequence identity in the 5' and 3' flanking regions, indicating that the transcriptional controls have been evolutionarily conserved.31 32 The high degree of nucleotide sequence homology in the 3' untranslated regions of human and canine IL-6 cDNA suggests that mechanisms controlling mRNA degradation23 24 and nuclear transport25 are conserved even when the coding regions have significantly diverged. Such a high level of regulation and control is likely to be important in IL-6 in light of the pleiotropic nature of its actions, the ubiquitous distribution of IL-6 receptors, and its involvement in orchestrating the response of the organism to incipient tissue injury or necrosis, otherwise known as the acute-phase response.35 36 37
The present studies document the upregulation of IL-6 mRNA in the previously ischemic myocardium, demonstrating that part of the inflammatory response that ensues as a result of ischemia and reperfusion is an increase in IL-6 mRNA expression. This induction occurs preferentially in ischemic and reperfused myocardial segments under conditions of significant blood flow reduction, while sparing the normally perfused control segments. The highest levels of induction observed were present in the most ischemic myocardial segments regardless of the reperfusion interval. Furthermore, an additional level of specificity was afforded by the observation that IL-6 was not induced in animals when coronary occlusion was not associated with blood flow reductions. These findings are consistent with previously reported patterns of induction of ICAM-1 mRNA under similar experimental conditions10 and with the time course of IL-6 cytokine activity present in cardiac lymph.9 Our findings are also consistent with the observed elevated levels of plasma IL-6 bioactivity in models of ischemia and reperfusion in other tissues.38
The association of myocyte ICAM-1 induction with IL-6 was originally made by our observations that the synthesis of ICAM-1 in cardiac myocytes stimulated by postreperfusion cardiac lymph was neutralized by a polyclonal antibody against human IL-6.9 Several lines of evidence presented in the study at hand strengthen this association. IL-6 mRNA is induced in the myocardium in the same ischemic segments in which ICAM-1 mRNA is found. IL-6 mRNA peaks in the first 3 hours of reperfusion, whereas ICAM-1 mRNA continues to increase for up to 24 hours.10 Thus, peak IL-6 mRNA levels in the myocardium precede those for ICAM-1 mRNA.10 The accelerating effect of reperfusion appears to be equally important for the early induction of both ICAM-1 and IL-6 genes in experimentally defined myocardial segments. In this regard, it is important to emphasize that this conclusion is supported by comparison with persistently ischemic myocardial segments. The role of IL-6 in the induction of ICAM-1 appears to be cell specific. Cardiac myocytes appear to be particularly sensitive to IL-6 stimulation9 : the concentrations of IL-6 required to induce ICAM-1 on myocytes are up to two orders of magnitude lower than those required for induction on liver cells and melanocytes.9 39 40 Furthermore, we have found that most of the ICAM-1 produced by liver cells was released into the supernatant; consequently, only minimal amounts remained on the cell surface.39 These findings, coupled with the inability of IL-6 to induce ICAM-1 on endothelial or epithelial cells,9 40 suggest that IL-6 may be a selective inducer of ICAM-1, with effects limited to specific parenchymal cells.
Expression of ICAM-1 on cardiac myocytes is possibly an important mechanism facilitating the cytotoxic potential of neutrophils for myocytes, since activated neutrophils are capable of directly damaging cardiac myocytes through CD11b/CD18–ICAM-1–mediated adhesion.6 This adhesive mechanism can be directly stimulated by the ability of recombinant IL-6 to induce ICAM-1 on cardiac myocytes.9 In addition, IL-6 effects may extend beyond the induction of ligand-specific adhesion of neutrophils to cardiac myocytes. IL-6 is devoid of a direct effect on neutrophils, but it has been shown to prime and enhance the neutrophil oxidative burst in response to chemotactic stimulation.41 This priming effect represents a potential complementary mechanism for IL-6 to facilitate neutrophil cytotoxic behavior in reperfused myocardium, in which the presence of complement-derived chemotactic factors and IL-8 has been demonstrated.7 8 41 42 43 44 Finally, recent reports have demonstrated elevated levels of IL-6 in patients with acute myocardial infarction45 46 and that clinically achievable levels of IL-6 could potentially cause reversible myocardial depression in the human heart.47
Our data imply that events initiated by reperfusion of the previously
ischemic myocardium are responsible for the rapid
and localized cytokine generation that ultimately results in
highly localized ICAM-1 mRNA expression.10 11 It is
well
known that one of the factors induced by reperfusion is a marked influx
of leukocytes into the ischemic area, resulting in dense
margination in cardiac venules followed by neutrophil
migration.3 10 48 49 50
We have proposed that
cytokine induction in the myocardium is dependent
on the postreperfusion influx of blood leukocytes.51 Both
neutrophils and monocytes are known to produce IL-6 in response to
stimulation by cytokines such as TNF- or
IL-1,52 53 and recent data also suggest that C5a
stimulation induces interleukin-6 synthesis in mononuclear
cells.54 This proposal is supported by the finding of IL-6
induction after 24 hours of persistent ischemia. By this time,
in contrast to permanent occlusions of only 4 hours, leukocytes have
densely infiltrated the infarcted area, even in the absence of
reperfusion.55 56 Although the augmented influx of
inflammatory cells may be responsible for IL-6 production, the
data suggest that the cytokine control of this process may
involve a more complex construct. Interestingly, the ability of cardiac
lymph to induce ICAM-1 in canine endothelial cells was
not inhibited by anti–IL-6 antibodies,9 leading us to
postulate the appearance of more than one cytokine in cardiac
lymph during reperfusion. The present results are best explained by
the presence of an "upstream" inducer capable of stimulating IL-6
synthesis; this would account for the ability of
postischemic cardiac lymph to induce IL-6 mRNA in
endothelial cells (Fig 6). The identity and source of
this putative "upstream" inducer remains to be determined. IL-6
induction may result from a complex cell
physiological event that ultimately allows
neutrophil-myocyte interactions via CD11b/CD18–ICAM-1
adhesion.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
These studies were supported by NIH grant HL-42550, by grants from The Methodist Hospital Foundation and Baylor College of Medicine (Dr Kukielka), and by the Lillie Frank Abercrombie Foundation (Dr Kukielka). The authors wish to acknowledge the assistance of J.L. Slightom and R.F. Drong with DNA sequencing and the assistance of Leonardo Mendoza, Lisa T. Thurmon, Peggy Jackson, Gary Liedtke, and Wei Chen with animal experiments and tissue culture.
|
Footnotes |
|---|
Reprint requests to Gilbert L. Kukielka, MD, Cardiovascular Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030-3498.
Guest editor for this article was Robert L. Engler, MD, San Diego (Calif) VA Medical Center.
Received July 18, 1994; revision received January 17, 1995; accepted April 5, 1995.
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References |
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