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(Circulation. 1999;99:546-551.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Cardiac Myocytes Produce Interleukin-6 in Culture and in Viable Border Zone of Reperfused Infarctions
From the Section of Cardiovascular Sciences, Department of Medicine, The DeBakey Heart Center, Section of Leukocyte Biology, Department of Pediatrics, and Texas Children's Hospital, Baylor College of Medicine, Houston, Tex.
Correspondence to Mark L. Entman, MD, Department of Medicine, Section of Cardiovascular Sciences, Baylor College of Medicine, One Baylor Plaza, M/S F-602, Houston, TX 77030-3498. E-mail mentman{at}bcm.tmc.edu
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Abstract |
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Background—Previous work from our laboratory demonstrated that interleukin (IL)-6 plays a potentially critical role in postreperfusion myocardial injury and is the major cytokine responsible for induction of intracellular adhesion molecule (ICAM)-1 on cardiac myocytes during reperfusion. Myocyte ICAM-1 induction is necessary for neutrophil-associated myocyte injury. We have previously demonstrated the induction of IL-6 in the ischemic myocardium, and the current study addresses the cells of origin of IL-6.
Methods and Results—In the present study, we combined
Northern blot analysis and in situ hybridization to demonstrate
IL-6 gene expression in cardiac myocytes. Isolated
ventricular myocytes were stimulated with tumor necrosis
factor-
, IL-1ß, lipopolysaccharide,
preischemic lymph, and postischemic lymph.
Unstimulated myocytes showed no significant IL-6 mRNA expression.
Myocytes stimulated with preischemic lymph showed minimal
or no IL-6 mRNA expression, whereas myocytes stimulated with tumor
necrosis factor-, IL-1ß, lipopolysaccharide, or
postischemic lymph showed a strong IL-6 mRNA induction.
Northern blot with ICAM-1 probe revealed ICAM-1 expression under every
condition that demonstrated IL-6 induction. We then investigated the
expression of IL-6 mRNA in our canine model of ischemia and
reperfusion. Cardiac myocytes in the viable border zone of a myocardial
infarction exhibited reperfusion-dependent expression of IL-6 mRNA
within 1 hour after reperfusion. Mononuclear cells infiltrate the
border zone and express IL-6 mRNA.
Conclusions—Isolated cardiac myocytes produce IL-6 mRNA in response to several cytokines as well as postischemic cardiac lymph. In addition to its production by inflammatory cells, we demonstrate that IL-6 mRNA is induced in myocytes in the viable border zone of a myocardial infarct. The potential roles of IL-6 in cardiac myocytes in an infarct border are discussed.
Key Words: interleukins • myocardial infarction • reperfusion • myocytes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Reperfusion of infarcted myocardium has been accepted as the treatment of choice for acute myocardial infarction and markedly accelerates the development of an inflammatory reaction in the infarcted tissue. Inflammation plays an important role in the healing of tissue after injury.1 2 3 4 5 6 7 8 9 However, there is evidence that the accelerated inflammatory response may also extend tissue injury. Clinical and experimental studies showed that the inflammatory response to myocardial infarction is associated with the induction of cytokines such as tumor necrosis factor (TNF)-
, interleukin
(IL)-1ß, and IL-6, which are thought to act in a "cascade
fashion."10 11 12 Our laboratory has focused on the cellular and molecular basis of the inflammatory reaction resulting from ischemia and reperfusion by using a strategy that integrates the insights from experiments done in cell culture with a disease model of myocardial ischemia and reperfusion in intact animal. Studies in our laboratory demonstrated a potential mechanism of neutrophil-induced myocyte injury. Neutrophils adhere to myocytes in the presence of intracellular adhesion molecule (ICAM)-1 on the myocytes and CD11b/CD18 on the neutrophils13 14 and mediate oxidative cytotoxicity for cardiac myocytes.15 With the use of a canine model in which we cannulated the cardiac lymph duct,16 17 we demonstrated that postischemic lymph contained cytokine activity capable of inducing ICAM-1 expression in cardiac myocytes in vitro. This activity could be abolished by neutralizing antibodies to IL-6.18
In the same model, we demonstrated that reperfusion-dependent induction of ICAM-1 mRNA occurred in the viable myocytes of the border zone of myocardial infarction.19 20 21
Subsequent studies showed an induction of IL-6 in the myocardium of a canine model of ischemia and reperfusion. IL-6 mRNA was found in the ischemic area and appeared to peak earlier on reperfusion. These studies demonstrated that IL-6 synthesis is an integral part of the reaction to injury resulting from ischemia and reperfusion and is associated with induction of ICAM-1 on the myocardial cells.21 22 IL-6 is produced by a variety of different cell types, including monocytes/macrophages, fibroblasts, endothelial cells, mast cells, neutrophils, keratinocytes, osteoblasts, and many more.23 In our previous work, we had reasoned that IL-6 mRNA induction was reperfusion dependent because of its association with the reperfusion-induced influx of leukocytes.22 24 25 The current study confirms the induction of IL-6 mRNA in mononuclear cells; however, it also provides the first direct demonstration that cardiac myocytes in vitro and in the viable border zone of a reperfused infarction also produce IL-6 mRNA.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Isolation of Cardiac Myocytes
The isolation of cardiac myocytes from healthy mongrel dogs of either sex was performed as described previously.13 18 The cells were resuspended with medium A and equilibrated with 95% O2/5% CO2. Preparations with a viability of >80% were used in the experiments. Nonmyocyte cells were <10% in all experiments.
The cell samples were incubated for 60 minutes at 37°C under one of
the following conditions: control, TNF- (100 U/mL), IL-1ß (200
U/mL), lipopolysaccharide (LPS) 50 µg/mL,
preischemic lymph (1:10 dilution), or
postischemic lymph (1:10 dilution). TNF- and IL-1ß
were obtained from Genzyme Corp. LPS was obtained from Sigma Chemical
Co. After the incubation, the cells were spun again, the supernatant
discarded, and the cells were immediately processed for RNA isolation
or for immunohistochemical studies.
All dishes and instruments used in the isolation process were pretreated with E-Toxa-Clean (Sigma Chemical Co) before sterilization to eliminate LPS contamination. Supernatants and solutions were periodically tested for LPS contamination with the E-Toxate Limulus LPS detection kit (Sigma Chemical Co), which is sensitive to 0.05 to 0.1 endotoxin units/mL. If the supernatants and solution showed a negative result with this test, they were considered uncontaminated, and only those preparations were used.
Ischemia-Reperfusion Protocols
Healthy mongrel dogs were surgically instrumented as described
in detail previously,16 17 21 with cannulation of the
cardiac lymph duct16 17 and placement of a hydraulically
occluding device and a Doppler flow probe secured around the
circumflex coronary artery just proximal or distal to the first
branch. The animals were allowed to recover for 72 hours before
occlusion. Coronary artery occlusion was achieved by inflating
the coronary cuff occluder until mean flow in the
coronary vessel was zero, which was determined by the
Doppler flow probe. For subsequent blood flow analysis,
radiolabeled microspheres were injected into the left atrium 50
minutes after occlusion. After 1 hour of occlusion, the cuff was
deflated and the heart was reperfused for up to 24 hours. Lymph samples
used for the myocyte experiment were collected from the cannulas in
tubes containing 10 U preservative-free heparin within 3 hours of
reperfusion. At the end of the reperfusion period, the heart was
stopped by infusion of saturated potassium chloride and removed
immediately and processed for RNA isolation or immunohistochemistry and
in situ hybridization as previously described.20 22
Adjacent sections were used for blood flow determination with
radiolabeled microspheres as previously
described.26 27 Analysis of RNA, blood flow
determination, and histopathology were performed independently in
different laboratories and in a blinded fashion. Sections used for
studies of infarction demonstrated infarction by histopathology and
ischemic blood flow of <20%.
All animal protocols were reviewed by the appropriate institutional review committee and conform to institutional guidelines.
Northern Blot Analysis
RNA was isolated from myocytes and myocardial tissue by use of
the acid guanidinium phenol chloroform procedure.28 RNA
was electrophoresed in 1% agarose gels containing formaldehyde, then
transferred to a nylon membrane (Gene screen Plus; New England Nuclear)
by standard procedure.29 Loading of RNA was monitored with
the use of ethidium bromide staining as well as by probing the nylon
membranes with glyceraldehyde 3-phosphate dehydrogenase
as previously described.22 Canine IL-6 cDNA and ICAM-1
cDNA were prepared as previously described.14 19 21 22
Immunohistochemical Methods
Samples were fixed in 4% formaldehyde, dehydrated by incubation
in increasing concentrations of ethanol with a standard protocol, and
then embedded in paraffin; 3- to 5-µm sections were obtained with
microtomy. For immunostaining, the slides were
rehydrated and incubated with hydrogen peroxide.
Immunostaining was performed with the Elite kit (Vector
laboratories), which has a peroxidase-based detection system. For
myoglobin, the color reaction was performed with AEC tablets from
Vector Laboratories as a substrate without counterstaining.
To define viable from nonviable cells, histological criteria such as contraction band necrosis and disrupted cell architecture were supplemented with specific histological stains. To distinguish further between infarcted and noninfarcted areas, serial sections to those used for in situ hybridization were immunostained for myoglobin with an antimyoglobin monoclonal antibody (rabbit anti-human antimyoglobin antibody; DAKO) and were stained for glycogen with PAS (periodic acid–Schiff).30 31 32
In Situ Hybridization
Riboprobes for canine IL-6 and ICAM-1 were prepared as
previously described.20 Digoxigenin-labeled probes were
prepared by in vitro transcription from a linearized template with the
Genius RNA probe labeling kit (Boehringer Mannheim Corp)
according to the manufacturer's instructions. A 215-bp [bases 483 to
697 of the published sequence22 ] fragment of canine IL-6
cDNA was obtained with polymerase chain reaction amplification and was
subcloned into the polymerase chain reaction plasmid (Invitrogen) so
that the use of SP6 polymerase would result in the generation of
single-stranded antisense (3'-5') and the use of T7 polymerase would
result in the generation of the sense (5'-3') probe. For the ICAM-1
probe, a 150-bp fragment was subcloned in both orientations into
PBluescript II Sk+ and PGEM-3 so that use of T7 polymerase would result
in the generation of single-stranded antisense (3'-5') and of the sense
(5'-3') probe.20 The procedure was the same as described
above for the IL-6 riboprobe.
The immunologic detection of the hybridized probe was done with the Genius detection kit from Boehringer Mannheim, following the guidelines of the company as previously described.20 The slides were stained with NBT and x-phosphate and then counterstained with eosin.
Statistics
Because of the characteristics of the experiments, raw data are
presented for each of the pertinent findings along with
controls. Each experiment presented was repeated at least 5
times with the same qualitative results.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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IL-6 Induction in Isolated Ventricular Myocytes: Northern Blot Analysis
The top panel of Figure 1
shows Northern blot analysis of mRNA isolated from
ventricular myocyte preparations under a variety of
experimental conditions. Marked IL-6 mRNA induction was noted in
myocytes incubated with TNF- (100 U/mL), IL-1ß (200 U/mL),
endotoxin (50 µg/mL), or cardiac lymph (diluted 1:10) collected
during the first hour after reperfusion of a myocardial infarction. In
contrast, cardiac lymph collected before the myocardial infarction
(preischemic lymph diluted 1:10) demonstrated minimal or no
induction of IL-6 mRNA in cardiac myocytes incubated under identical
conditions. All samples were incubated at 37°C for 1 hour.
Unstimulated control myocytes kept at room temperature for 1 hour never
showed IL-6 mRNA expression. However, after incubation at 37°C for 1
hour, a minimal induction of IL-6 was sometimes observed and was always
much lower than in the stimulated myocytes (data not shown).
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Because of our previous association of IL-6 with induction of myocyte
ICAM-1,19 we also analyzed the same Northern blots
for ICAM-1 mRNA induction (Figure 1
, bottom). In every case,
ICAM-1 mRNA expression matched expression of IL-6 mRNA
qualitatively.
In Situ Hybridization Studies of IL-6 mRNA Expression in Isolated
Cardiac Myocytes
Serial sections through fixed ventricular myocytes
treated identically to those used in the Northern blot analysis
were examined for IL-6 induction with a sense and antisense riboprobe
as described in "Methods." The unstimulated cardiac myocytes
(control) showed no significant staining with the IL-6 antisense probe.
Myocytes stimulated with TNF-, IL-1ß, or endotoxin showed a
significant amount of staining with the antisense probe; no staining
was seen with the use of the IL-6 sense riboprobe as a control (Figure 2). Incubation of cardiac myocytes with
the preischemic cardiac lymph showed little or no staining
with the IL-6 antisense riboprobe, but postischemic cardiac
lymph collected over the first 3 hours of reperfusion in the same
dilution was capable of robust induction of IL-6 mRNA in myocytes
(Figure 2).
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In Situ Hybridization Assessment of IL-6 mRNA Induction in
Intact Myocardium
In Figure 3, serial sections
are examined from an experiment of 1 hour of ischemia and 3
hours of reperfusion. In Figure 3D, PAS staining demonstrates an
area of predominant glycogen depletion adjoining areas of viable
myocardial cells with relatively preserved glycogen on the epicardial
aspect of the infarct (arrowheads) and in the innermost layers of the
subendocardium (arrows). In situ hybridization studies for IL-6 in
panel A show significant IL-6 mRNA induction in viable myocardial cells
found in the spared innermost layers of the endocardium (arrows) as
well as on the epicardial border zone (arrowheads). The presence of
this preserved layer at the innermost portion of the
myocardium has been previously reported.32
Higher magnification (Figure 3C) demonstrates that this staining
for IL-6 mRNA is seen in both the myocardium as well as
(more intensely) in infiltrating mononuclear cells. Panel E (compared
with panel A) demonstrates that ICAM-1 mRNA induction is seen in the
same regions of viable myocytes on the border zone of the myocardial
infarct. The colocalization of IL-6 mRNA and ICAM-1 mRNA induction is
almost complete at 3 hours of reperfusion.
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Induction of IL-6 mRNA in myocytes could be demonstrated by 1 hour of
reperfusion (Figure 4) and was
consistently found in viable areas abutting the area of
contraction band necrosis. Note that in addition to the spared
subendocardium and epicardial border zone, there is a region (within
the infarct) surrounding a small vessel (arrow) that is preserved
(retains glycogen) and expresses IL-6 mRNA.
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Figure 5 represents serial
sections taken from an animal after 1 hour of ischemia and 24
hours of reperfusion. The architectural features are almost identical
to those seen at 3 hours of reperfusion, although there is greater
infiltration of mononuclear cells into the infarct, and these cells
produce IL-6 mRNA as described above (data not shown). The figure again
demonstrates the preserved subendocardial cells expressing IL-6
mRNA.
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In the absence of reperfusion, no significant staining of IL-6 mRNA was
detected either at 1 hour, 2 hours (data not shown), or 4 hours (Figure 6) of ischemia. This was
compatible with our previous observation of reperfusion dependence of
IL-6 mRNA induction.19 22
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our study combines in vitro data with isolated cardiac myocytes and in vivo data with our canine ischemia/reperfusion model and clearly demonstrates that myocytes can express message for IL-6 in our experimental setting. Various cytokines as well as postischemic lymph are capable of inducing IL-6 mRNA in the isolated myocytes. To the best of our knowledge, this is the first direct histological demonstration of IL-6 mRNA production in the adult cardiac myocyte, both in vitro and in vivo. These data are compatible with a recent observation with Northern blots,33 suggesting that cultured neonatal cardiac myocytes respond to hypoxic stress by IL-6 production.
Guillen et al10 demonstrated the sequential increase in
IL-1ß and IL-6 after myocardial infarction, suggesting an inducer
function of IL-1ß for IL-6. TNF- is also upregulated in myocardial
infarction and may also induce IL-6
production.34 35 In previous work, we have
demonstrated that there is a rapid increase in TNF- in
postischemic lymph and that TNF- is released from
preformed stores in cardiac mast cells.36 In our model, we
found no evidence for the early presence of IL-1.36
TNF- is a known inducer of IL-6 in endothelial
cells, fibroblasts, and mononuclear cells,36 37 38 39 and, in
the present study, we could demonstrate that it also induces IL-6
gene expression in cardiac myocytes. We suggested that TNF- may act
as an upstream cytokine inducer of IL-6 in
ischemia/reperfusion.
Investigation of IL-6 induction demonstrated reperfusion dependence.
Northern blot analysis suggested that IL-6 induction preceded
ICAM-1 induction in the reperfused infarct.19 22 Because
both IL-6 and ICAM-1 induction were reperfusion dependent within the
first 6 hours, we postulated that IL-6 production was most
likely occurring in infiltrating leukocytes that would not be
present in the absence of reperfusion. Indeed, we have demonstrated
that mononuclear cells found within postischemic cardiac
lymph demonstrate IL-6 mRNA induction within 15 minutes of
reperfusion.36 40 The current studies demonstrate that
mononuclear cells in tissue stained intensely in an in situ
hybridization reaction with an IL-6 riboprobe (Figure 3C).
However, it became obvious that IL-6 mRNA was being induced (at lower
intensity) in cardiac myocytes in the viable border zone.
Relation of Cellular Source of IL-6 to ICAM-1 Induction
The exceptional colocalized induction of IL-6 and ICAM-1 at 3
hours invites consideration of an autocrine mechanism for some of the
observed ICAM-1 mRNA induction. It is unlikely, however, that all of
the ICAM-1 induction is autocrine. In Figure 5, examination of
reperfusion after 24 hours shows that IL-6 mRNA remains confined to
cardiac myocytes on the border zone of the myocardial infarction. In
contrast, in our previous studies, examination of the reperfused
myocardial infarction after 24 hours of reperfusion demonstrated ICAM-1
mRNA in all of the cardiac myocytes.20 This correlated
with our observation that postischemic cardiac lymph
retained its ability to induce ICAM-1 for up to 72 hours after
reperfusion and was quite high at 24 hours. The induction of ICAM-1
mRNA in the "normal" myocardium might appear to result
from IL-6 in the extracellular fluid and blood as observed by us and
other laboratories.10 11 12 18 An autocrine contribution to
early ICAM-1 induction in the border zone remains a possibility.
IL-6 Effect on Cardiac Function
Recent studies suggest that "inflammatory cytokines"
may exert primary effects on myocardial function. Finkel and his
coworkers41 42 have demonstrated that IL-6 may act as a
nitric oxide–dependent cardiac depressant and may be associated with
stunned myocardium.42 IL-6 has produced a
nitric oxide–mediated reduction in calcium flux and
contractility in chick ventricular
myocytes.43
IL-6 is a member of a class of cytokines whose receptor mechanisms share the presence of a common protein, gp130.44 Two members of this family, cardiotrophin and leukemia inhibitory factor, have been shown to induce cardiac hypertrophy.45 46 These agents work through the JAK/STAT pathway induced by gp130. Transgenic mice double overexpressing IL-6 and IL-6 receptor also demonstrate myocardial hypertrophy.47 In addition to their effect on hypertrophy, these cytokines have been shown to be cytoprotective against apoptosis. Cardiotrophin prevents apoptotic cell death induced by serine depletion in neonatal rat cardiac myocytes.48 49 Overexpression of IL-6 and IL-6 receptor has been demonstrated to be cytoprotective in cell systems through induction of the antiapoptotic gene bcl-xL, and LIF has been demonstrated to exert an antiapoptotic effect in cardiac myocytes through induction of the same gene.50 51 It is interesting to speculate that these 3 responses, reduced contractility, positive protein balance (hypertrophy), and antiapoptosis, might favorably influence myocardial cells and allow them to survive in an area of jeopardy.
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Acknowledgments |
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This work was supported by NIH grant HL-42550. The authors wish to thank Concepcion Mata and Sharon Malinowski for their editorial assistance with the manuscript and Peggy Jackson, Alida Evans, and Etai Funk for their outstanding technical expertise.
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Footnotes |
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Guest Editor for this article was Robert Engler, MD, Collateral Therapeutics, San Diego, Calif.
Received March 4, 1998; revision received August 25, 1998; accepted September 16, 1998.
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