(Circulation. 2000;102:1697.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Direct Evidence for Cytokine Involvement in Neointimal Hyperplasia
From the University of Florida College of Medicine, Malcom Randall VAMC, Gainesville, Fla.
Correspondence to C. Keith Ozaki, MD, PO Box 100286, Gainesville, FL 32610. E-mail ozaki{at}surgery.ufl.edu
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Abstract |
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Background—Tumor necrosis factor-
(TNF-) and interleukin 1 (IL-1) are proximal inflammatory
cytokines that stimulate expression of adhesion molecules and
induce synthesis of other proinflammatory cytokines. In
addition, TNF- and IL-1 influence vascular smooth muscle cell
migration and proliferation in vitro. In view of the inflammatory
nature of neointimal hyperplasia (NIH), we tested the
hypothesis that endogenous TNF- and IL-1 modulate low
shear stress–induced NIH.
Methods and Results—Mice underwent unilateral common carotid
artery (CCA) ligation. Low shear stress in the patent ligated CCA has
previously been shown to result in remodeling and NIH. Reverse
transcriptase–polymerase chain reaction for TNF- and IL-1 mRNA
demonstrated both TNF- and IL-1 mRNA in ligated CCAs, whereas
normal and sham-operated CCAs had none. Mice lacking functional TNF-
(TNF-/-) developed 14-fold less neointimal area than WT
controls (P<0.05). p80 IL-1 type I receptor knockout
(IL-1RI-/-) mice tended to develop less (7-fold,
P>0.05) neointimal area than WT controls.
Furthermore, no IL-1 mRNA expression was detected in CCAs from
TNF-/- mice; however, TNF- mRNA expression was found in the
IL-1RI-/- mice. Mice that overexpress membrane-bound TNF- but
produce no soluble TNF- display an accentuated fibroproliferative
response to low shear stress (P<0.05).
Conclusions—These results directly demonstrate that TNF- and
IL-1 modulate NIH induced by low shear stress. NIH can proceed by way
of soluble TNF-–independent mechanisms. Specific anti–TNF- and
anti–IL-1 therapies may lessen NIH.
Key Words: remodeling • restenosis • atherosclerosis • carotid arteries
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Introduction |
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Myofibroblast migration into the intima followed by proliferation and matrix deposition (neointimal hyperplasia, NIH) is a central feature of early atherosclerosis, restenosis, and bypass graft failure.1 2 3 Most prior research focused on the biochemical mechanisms of NIH, although various mechanical forces on the arterial wall can also result in this fibroproliferative response.4 For example, intimal thickening and atherosclerosis tend to occur in areas of low wall shear stress, such as the carotid bifurcation.5 Complete signaling pathways from biomechanical fluid forces to changes in arterial cell biology have not been completely dissected.
Multiple lines of research suggest that NIH occurs by way of
inflammation-dependent mechanisms.6 Circumstantial
evidence links the proinflammatory cytokines tumor necrosis
factor- (TNF-) and interleukin-1 (IL-1) to these
processes.7 8 9 10 11 TNF- induces a substantial increase in
expression of intercellular adhesion molecule-1 (ICAM-1) by human
smooth muscle cells (SMCs) in vitro.3 12 Elevated TNF-
expression has been localized to areas of arterial
injury.11 13 14 Similarly, increased levels of TNF-
precede migration of SMCs into the intima in the balloon-injured rat
aorta by several days.13 TNF- levels have been found to
be elevated in atherosclerotic artery specimens.15
TNF-–soluble receptor, a TNF- antagonist, has been
used to inhibit coronary artery neointima formation
in cholesterol-fed rabbits that had previously undergone
cardiac transplantation.16 However, information from this
model, which relies primarily on dietary manipulation and transplant
immunology, may not be relevant for other situations of
arterial remodeling.
IL-1 functions as a growth factor for fibroblasts,
keratinocytes, lymphocytes, and SMCs and enhances
activation of B and T cells,17 18 many of the cell types
implicated in inflammation and NIH. More importantly, IL-1 is an
activator of endothelial cell gene
expression and is known to modulate the presence of cell adhesion
molecules such as E-selectin on the endothelial
surface.19 Finally, both TNF- and IL-1 increase LDL
binding to endothelium and smooth
muscle6 20 and increase transcription of the LDL-receptor
gene.21 Whether TNF- and IL-1 have primary direct roles
in vivo in regulating low shear stress–induced NIH or are involved
secondarily remains uncertain.
In view of the inflammatory characteristics of NIH and the known
central signaling roles played by the proinflammatory cytokines
TNF- and IL-1, we hypothesized that NIH proceeds by way of TNF-
– and IL-1–dependent mechanisms. Specifically, we hypothesized that
low shear stress would induce TNF- and IL-1 expression and NIH and
that mice lacking either functional TNF- or IL-1 would develop less
neointima than wild-type controls. Moreover, we
hypothesized that TNF- modulation of NIH can proceed by way of
soluble TNF-–independent mechanisms and that overexpression of
membrane-bound TNF- will exacerbate the hyperplastic response to low
shear stress.
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Methods |
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Overall Experimental Strategy
The absence of TNF-
and IL-1 in the quiescent artery wall and
their expression after induction of low shear stress were documented by
use of the reverse transcriptase–polymerase chain reaction (RT-PCR).
The consequences of lack of TNF- and IL-1 were ascertained in
transgenic mice expressing null forms of these cytokines or
their receptors. The dependence of signaling on soluble TNF- was
investigated in mice that produce only the membrane-bound form of
TNF-. Finally, in an effort to better define signaling relationships
between TNF- and IL-1 in low shear stress–induced NIH, TNF- and
IL-1 mRNA expression was assayed in these transgenic mice.
Murine Model of Low Shear Stress–Induced NIH
A total of 24 TNF-null mice (TNF-/-),22 21 IL-1
receptor I–null mice (IL-1RI-/-),23 14
tgA86xtnf-
-/-
mice,24 and 101 B6x129 wild-type (WT) mice were used
to carry out the following experiments. Mice were male and 7 to 13
weeks of age. Each transgenic mouse strain used was on a B6x129
background, and all (TNF-/-, IL-1RI-/-, and
tgA86xtnf-
-/-) were maintained
by brother-sister matings, as were B6x129 controls. Mice were
anesthetized with inhaled methoxyflurane, then placed under
anesthesia with 1.25% isoflurane. A midline neck incision
was made and the left common carotid artery (CCA) carefully dissected
out under an operating microscope. The left CCA was ligated with a 6-0
silk ligature just proximal to its bifurcation. The mouse was allowed
to recover and was maintained on standard chow diet. This model
reproducibly results in NIH in the presence of an intact
endothelial cell lining, with an 80% reduction in
luminal area by 4 weeks.25 26 We (and
others25 26 ) have confirmed that this
neointima is not thrombus that recanalizes. Intimal SMC
replication rates average 
25% by day 5 after ligation, and the
number of intimal cells peaks after 14 days.25 At specific
time points after the initial surgery, the mice were again
anesthetized by the same technique, and bilateral CCAs were
removed.
For morphometric studies, CCAs were perfusion-fixed over 1 second with
0.25 mL of 10% formalin via cardiac puncture. Specimens were embedded
in paraffin. Five representative sections from the
entire 5-mm CCA (1 section per 800 µm) then underwent Masson
staining. The section containing the largest neointima
(reflection of the tendency of the artery to develop NIH) underwent
quantitative analysis. Digitalized images of these vessels were
obtained and analyzed with analysis software (Zeiss
Image, Version 3.0). The lumen, internal elastic lamina (IEL), and
external elastic lamina (EEL) were defined, and the intima (tissue
between lumen and IEL) and media (tissue between IEL and EEL) areas
were recorded.25 Intima/media area ratios were also
calculated.
TNF- and IL-1 Expression Due to Low Shear Stress
WT mice were euthanized at 1 (n=9), 7 (n=10), and 28 (n=4) days
after ligation, and TNF- mRNA was assayed by RT-PCR. Additional WT
mice were euthanized at 1 (n=5), 4 (n=5), 7 (n=5), 10 (n=5), and 14
(n=5) days after surgery, and IL-1 mRNA was assayed by RT-PCR.
In an attempt to better dissect signaling pathways, the presence of
IL-1 mRNA in the ligated CCAs of the TNF-–null mice and TNF-
mRNA in the ligated CCAs of IL-1RI–null mice was examined. TNF-/-
mice (n=10) were euthanized 10 days after ligation, and the IL-1RI-/-
(n=8) mice were euthanized 1 week after surgery. Time points for
detection were based on results from the previous experiment.
Reverse Transcriptase–Polymerase Chain Reaction
All CCAs were flushed with PBS before harvest and then
snap-frozen in liquid nitrogen. Because of the small quantity of
tissue, all left and all right CCAs were pooled into separate groups of
4 or 5 CCAs for each time point in each specific study group. Total
cellular RNA was isolated.27 RT-PCR was performed with a
GeneAmp RNA PCR Core Kit (PE Applied Biosystems). Five micrograms of
each RNA sample was reverse-transcribed in a 40-µL reaction with
5 mmol/L MgCl2, 1x PCR Buffer II, 1
mmol/L dNTPs, 1 U/µL RNase inhibitor, 2.5 U/µL MuLV
reverse transcriptase, and 2.5 mol/L oligo
d(T)16. The reactions were incubated in a thermal
cycler 480 at 28°C for 10 minutes to allow for oligo d(T) binding,
42°C for 60 minutes for reverse transcription, and 95°C for 5
minutes to inactivate the reverse transcriptase. One to 4
µL of the cDNA stock, equivalent to 0.125 to 0.5 µg of
reverse-transcribed RNA, was used in the subsequent PCR reactions. PCR
was carried out in 50-µL reactions with 2 mmol/L
MgCl2, 1x PCR Buffer II, 0.2 mmol/L dNTPs,
1.25 U AmpliTaq DNA polymerase, and 50 pmol of the specific
oligonucleotide primers. The primers used for mTNF-
were 5'-ATGAGCACAGAAAGCATGATC-3' and 5'-TACAGG-CTTGTCACTCGAATT-3',
and for Cu/Zn superoxide dismutase, 5'-GTGTGCGTGCTGAAGGGCGAC-3' and
5'-TCTCCTGAGA-GTGAGATCACA-3' (a stable-expression
"housekeeping gene"). The mIL-1 primers used in this experiment
were 5'-GTCTCAC-TACCTGTGATGAGT-3' and
5'-AAGTTTGTCATGAATGATT-CCCTC-3'.
Optimal PCR temperature profiles were used for each of the different genes examined: a single cycle at 94°C for 2 minutes; a variable number of cycles with 1 minute at 94°C (denaturing), 1 minute at 60°C (annealing), and 2 minutes at 72°C (extension); and a final cycle at 72°C for 7 minutes. The PCR products were electrophoresed on a 2% agarose gel containing 0.4 µg/mL ethidium bromide.
TNF- – and IL-1–Deficient Mice
To determine the effects of the absence of TNF- and IL-1 in
low shear stress–induced NIH, TNF-/- (n=14), IL-1RI-/- (n=8), and
WT (n=43) mice underwent CCA harvest and morphometric analysis
4 weeks after ligation. The same tests in control WT mice were
run concurrently with each cohort of transgenic mice.
Soluble TNF-–Deficient Mice
Transgenic tgA86 mice contain a
site-directed deletion of the amino acids +1 through +12 in the gene
coding for murine TNF-. The resultant transgenic mouse possesses a
mutation at the TNF-–converting enzyme (TACE) cleavage site and is
incapable of processing mTNF- into the soluble form. Reinsertion of
the mutated gene into a TNF-–null mouse
(tnf--/-)
results in a transgenic mouse
(tnf--/-xtgA86)
that contains multiple copy numbers (50) of the
tgA86 gene and overexpresses only
mTNF-.24
tnf--/-xtgA86
mice (n=14) and WT controls underwent CCA harvest and morphometric
analysis 4 weeks after ligation. The same tests in control WT
mice were run concurrently with each cohort of transgenic mice.
Immunohistochemical Analyses
Harvested CCAs were embedded in paraffin for immunohistochemical
analysis 4 weeks after ligation. -SMC actin antibody kits
(Sigma) were used for identification of SMCs within the
neointima and media.
Statistical Analysis
Differences in neointima formation in WT versus
TNF-/-, IL-1RI-/-, and tgA86 mice
were determined by Kruskal-Wallis ANOVA on ranks and then Dunn’s
multiple comparison.
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Results |
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TNF-
Expression Due to Low Shear StressTNF-
mRNA was evident by RT-PCR (nonquantitative) in the
ligated CCAs of WT animals at 7 days after surgery (Figure 1A
). No mRNA for TNF- was found in the
unligated CCAs at 1, 7, or 28 days or in the ligated CCAs at 1
and 28 days. No baseline expression of TNF- was found in native CCAs
before operation or in sham-operated animals (Figure 1C), and
results were duplicated in an independent experiment.
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IL-1 Expression Due to Low Shear Stress
IL-1 mRNA was found by RT-PCR (nonquantitative) in the ligated
CCAs of WT mice at 4, 7, 10, and 14 days after ligation (Figure 1B
). No IL-1 mRNA was noted in unligated CCAs or in the ligated
CCAs 1 day after surgery. No baseline expression of IL-1 was found
in native CCAs before operation or in sham-operated animals (Figure 1C), and the results were duplicated in an independent
experiment.
Lack of Endogenous TNF- and NIH
Intimal areas for TNF-/- mice were significantly less than for
WT mice (Figures 2 and 3). The mean intimal area for TNF-/-
mice was 0.002±0.001 mm2, compared with
0.028±0.004 mm2 (mean±SEM) for WT mice
(P<0.05). This 14-fold decrease in neointima
formation in knockout mice was confirmed by comparison of
intima-to-media ratios (0.051±0.034 for TNF-/- versus 0.984±0.148
for WT, P<0.05).
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Lack of Endogenous IL-1 and NIH
Intimal areas for IL-1RI-/- mice tended to be less than those of
WT mice (Figures 2 and 3), although this trend failed to
reach statistical significance by multiple-comparison methods. Compared
solely with the WT results by the Mann-Whitney rank-sum test, the
difference is highly significant (P=0.009). The mean intimal
area for IL-1RI-/- mice was 0.004±0.002
mm2, compared with 0.028±0.004
mm2 (mean±SEM) for WT mice. The 7-fold decrease
in neointima formation in the IL-1RI-/- animals was
confirmed by comparison of intima-to-media ratios (0.115±0.057 for
IL-1RI-/- versus 0.984±0.148 for WT).
Lack of Soluble TNF- and NIH
tnf--/-xtgA86
mice developed 2.8-fold more neointima than corresponding
tnf-+/+ WT (0.081±0.017
versus 0.028± 0.004 mm2, mean intimal
area±SEM, P<0.05, Figures 2 and 3).
Intima-to-media ratios confirmed more intima in the
tnf--/-xtgA86
versus tnf-+/+ animals
(2.263±0.395 versus 0.984±0.148, P<0.05). Both the
tnf--/-xtgA86
and WT (tnf-+/+) mice
contained similar amounts and distribution of -SMC
actin–positive cells within the neointima.
IL-1 Expression in TNF-/- Mice
No IL-1 mRNA was found in either the ligated or unligated CCAs of
pooled TNF-/- mice 10 days after surgery (Figure 1C), the time
point at which IL-1 mRNA appeared to peak in the ligated carotid of WT
animals. Results were duplicated in an independent experiment.
TNF- Expression in IL-1RI-/- Mice
mRNA for TNF- was detected in the ligated CCAs of IL-1RI-/-
mice 7 days after surgery, the time point at which TNF- was
present in the ligated CCAs of WT animals (Figure 1C).
Results were duplicated in an independent experiment.
Immunohistochemical Analysis
WT controls exhibited a large amount of neointima
containing -SMC actin–positive cells. Analysis of the
ligated CCAs in TNF-/- animals revealed -SMC actin–positive cells
within the small amount of neointima formed. Of the 8
IL-1RI-/- mice that survived the initial surgical ligation, only 1
carotid showed evidence of NIH (Figure 3). -SMC actin
staining of this carotid demonstrated the presence of
myofibroblasts.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although both in vitro and in vivo observations correlate inflammation with the arterial wall response to "injury" (chemical or mechanical),3 6 13 15 16 20 21 few directly address whether the fibroproliferative response occurs by way of inflammatory pathways or whether the inflammation is secondary to some other driving mechanism. Arguments that atherosclerosis and NIH are inflammatory phenomena suggest an important role for the cytokines TNF-
and IL-1 in
this process. A recently described murine model of NIH,25
coupled with the development of transgenic mice lacking functional
TNF- and IL-1, allowed us to more clearly identify the role of
TNF- and IL-1 in low shear stress–induced NIH. Our results of
experiments in the intact animal demonstrate that lowered shear stress
induces local arterial wall expression of both TNF- and
IL-1 and that without biologically active TNF- or IL-1 signaling
pathways, NIH is greatly attenuated. Lack of IL-1 mRNA expression in
TNF-/- animals suggests that IL-1 induction in response to low
shear stress may occur by way of TNF-–dependent mechanisms.
However, more detailed time course experiments (IL-1 message
appeared before TNF- message in the RT-PCR experiments) and
investigation of IL-1ß will be necessary to verify this relationship
that has been noted in prior in vitro experiments.9
Transgenic mice lacking functional TNF- and IL-1 have added much to
the knowledge of the properties of both TNF- and IL-1 and their
receptors.22 23 Both TNF-/- and IL-1RI-/- mice are
phenotypically normal. The TNF-/- mice cannot produce biologically
active TNF- and do not die when exposed to
lipopolysaccharide (LPS)–induced sepsis,22 and
the IL-1R1-/- mice failed to respond to IL-1 in a number of
assays. IL-1RI -/- mice do not exhibit an upregulation of E-selectin,
vascular cell adhesion molecule-1 (VCAM-1), or other
endothelial cell adhesion molecules on stimulation with
IL-1 but do express these molecules on stimulation with
LPS.23
TNF- exists in 2 biologically active forms: a soluble form and a
membrane-bound form. Both are capable of signaling through the TNF type
1 and 2 receptors. TNF- is produced in the cell in a 33-kDa form. It
is then modified to a 26-kDa form and inserted into the cell membrane,
resulting in membrane-bound TNF-. Membrane-bound TNF- can then be
cleaved by TACE into a 17-kDa soluble form. Transgenic
tgA86 mice contain a site-directed
deletion, leading to TACE resistance. Reinsertion of the mutated gene
into a TNF-–null mouse
(tnf--/-)
results in a transgenic mouse
(tnf--/-x
tgA86) that contains multiple copy
numbers (50) of the tgA86 gene and
thus overexpresses mTNF-.24 The exacerbated
fibroproliferative response observed in these mice may be due to this
overexpression of this proinflammatory cytokine.
Potential limitations to our studies exist. The transgenic mice may compensate for defective signaling pathways by altering transcription and translation of related proteins. These proteins could have a secondary effect on low shear stress–induced signaling. Also, although the arteries were followed for NIH well past the time point at which it usually initiates in this model, we cannot rule out an extreme delay in the formation of an equivalent amount of neointima in the mice lacking proinflammatory cytokines. Working in murine models poses limitations on traditional molecular techniques. For instance, recovery of sufficient RNA for Northern analysis, even with pooled samples, is impractical. Finally, differences in platelet function may exist among the various mouse genotypes studies. We have found murine platelet studies difficult to reproducibly complete.
TNF- signaling probably potentiates NIH due to low shear stress by
multiple mechanisms. TNF- induces expression of a host of
biologically active molecules that may accentuate the
fibroproliferative response to injury: ICAM-1 and other cell adhesion
molecules, prostanoids, and other cytokines.3 14
At the cellular level, TNF- expression by medial SMCs precedes their
proliferation in a rabbit balloon-injury model, suggesting that TNF-
may contribute to their activation, migration, and
proliferation.14 This may occur by way of
mitogen-activated protein kinase mechanisms.28
Inflammatory cytokines can activate nuclear factor-
B
in vitro, and nuclei of human atheroma intimal SMCs contain
nuclear Rel family members p65 or p50 protein, whereas normal artery
sections do not.29 More mediators of TNF- signaling are
being identified by molecular techniques, such as differential
display.30 Finally, TNF- stabilizes IL-1 mRNA, thereby
possibly accentuating IL-1–driven mechanisms of
NIH.31
The mechanisms by which IL-1 influences neointimal
formation most likely occur at several levels. First, IL-1 may have
effects at the level of cellular adhesion. In one study, E-selectin
mRNA was demonstrated to be significantly elevated in the kidney, lung,
and heart of normal mice after treatment with exogenous
IL-1.23 Because mice lacking the functional p80 type I
receptor do not upregulate E-selectin or VCAM-1,23
leukocyte rolling, firm adhesion, and diapedesis may not occur. In
vitro experiments using prestimulated SMCs and normal
endothelial cells showed a reduced migration of
peripheral blood mononuclear cells into the
subendothelial space after treatment with antibodies to
IL-1.32 Inflammatory cells critical to NIH (such as
macrophages and T helper cells) may be unable to localize to
the site of injury and initiate a full inflammatory response. In
addition, IL-1 is a growth factor for several cell lines and is known
to enhance activation of both T and B cells. The role of T helper cells
in inflammation and atherosclerosis is well
defined.6 In the absence of IL-1, T cells may remain
unactivated or only partially activated and may not be
capable of contributing to and propagating the inflammatory response
and subsequent NIH. IL-1 can act as a mitogen for vascular
SMCs18 and sustain arterial wall inflammation
by inducing IL-1 gene expression.33 In our experiments,
the IL-1RI-/- CCAs had few -SMC actin–positive cells within the
small amount of neointima (if any) present. IL-1
receptor antagonist, a member of the IL-1 family and
specific for both IL-1 and IL-1ß, has been shown to reduce rat
vascular SMC proliferation in vitro.34 As additional
support of a role for proinflammatory cytokines in NIH, both
exogenous TNF- and IL-1 induced neointima formation in
normal porcine coronary arteries.10 Our data do
not define whether the low shear stress–induced TNF- and IL-1
signalings are confined to the artery wall or more systemic in
scope.
In summary, these experiments in the intact animal demonstrate that
TNF- and IL-1 modulate low shear stress–induced NIH, thus providing
a direct proinflammatory cytokine signaling link between
biomechanical forces to a blood vessel wall and the remodeling response
of the artery. The mechanical force of lowered shear stress induces
local arterial wall expression of both cytokines.
These signaling pathways can proceed by way of soluble
TNF-–independent mechanisms. Without biologically active TNF- or
IL-1 signaling pathways, NIH is greatly attenuated, and it is
exacerbated when mTNF- is overexpressed. Specific anti–TNF- and
anti–IL-1 therapies may lessen NIH.
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Acknowledgments |
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This study was supported by NIH-1T32-GM08721–01, NIH-GM-40586, VA Medical Research Merit Review, and the Howard Hughes Medical Institute Research Resources Program. We acknowledge Cynthia L. Tannahill, MS, and Zaher Abouhamze, BS, for technical assistance and Carl K. Edwards III, PhD (Amgen, Inc, Thousand Oaks, Calif), for providing TNF-/- and tnf-
-/-xtgA86
mice. Received February 16, 2000; revision received April 17, 2000; accepted May 5, 2000.
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