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*
Institute of Medical Microbiology and Hygiene and
Department of Internal Medicine, Division 1, Section of Pathophysiology, Johannes Gutenberg-University of Mainz, Mainz, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Smooth muscle cells (SMC) actively participate in local and systemic inflammatory reactions, thereby undergoing characteristic phenotypical changes (14, 15, 16). Activated SMC proliferate (15, 16, 17, 18), migrate (19, 20, 21), up-regulate adhesion molecules (22), and secrete cytokines (17, 23, 24). These processes have been most often related to the action of platelet-derived growth factor (PDGF), fibroblast growth factor ß (FGF-ß), or IL-1 (17, 19, 20, 23, 25, 26, 27). Some studies additionally indicate that SMC can be activated by IL-6 (17), but the underlying basis has not been explored, and it is not known whether these cells express either the complete IL-6R or gp130. In this study, we identify SMC as the first example of cells in which gp130 is subject to substantive up-regulation. It is shown that IL-6/sIL-6R up-regulate gp130 expression, and an autocrine loop is created via which IL-6/sIL-6R drive SMC into a proinflammatory state. This process may be relevant in many inflammatory situations involving the vascular system including vasculitis, transplant rejection, and atherosclerosis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vascular SMC were derived from pieces of human aortas obtained
during aneurysm surgery (12 donors, mean age 72 years, 9 male/3 female)
by courtesy of Dr. W. Schmiedt (Department of Heart and Thoracic
Surgery, University of Mainz). Isolated media fragments were prepared
by stripping off the endothelial cell layer, the adventitia, and
removal of all necrotic and calcified material (28). SMC
were allowed to grow out from the media fragments that were kept in
medium containing 1 ng/ml human recombinant basic FGF-ß, 5 ng/ml
human recombinant epidermal growth factor, 25 mg/L gentamicin, and 1.25
mg/L amphotericin B at 37°C in 5% CO2 in a
humidified atmosphere. The purity of SMC was evaluated by staining with
a mAb directed against SMC-specific 
-actin (clone 1A4; Sigma) and by
the typical elongated cell morphology with hill and valley appearance.
Twenty-four hours before experiments, SMC were grown in DMEM (Life
Technologies, Karlsruhe, Germany) without any additives. All
experiments were performed after less than five passages of culture
(29). Viability of cells was assayed using trypan blue
exclusion.
Reagents
Highly active fusion protein of human IL-6 covalently linked to the human sIL-6R (Hyper-IL-6), human IL-6, and human sIL-6R were prepared as previously described (30, 31, 32). Neutralizing monoclonal anti-human monocyte chemoattractant protein (MCP)-1 Ab (clone 24822.111, IgG1) was obtained from R&D Biosystems (Abingdon, U.K.). PE-labeled anti-gp130 (clone AM64, IgG1) was obtained from PharMingen (San Diego, CA). The FITC-labeled anti-human ICAM-1 (clone 84H10, IgG1) and anti-human E-selectin (clone 1.2B6, IgG1) Abs were obtained from Camon (Wiesbaden, Germany). A FITC-labeled mouse monoclonal IgG1 Ab (clone 11711.11) was used as an isotype control for nonspecific staining (R&D Biosystems).
RT-PCR of chemokine and cytokine mRNA
Total cellular RNA was isolated from confluent SMC cultures by
guanidine isothiocyanate-phenol-chloroform extraction as described by
Chomczynski and Sacchi (33). Reverse transcription of 1
µg of total RNA was conducted in a 20-µl reaction volume using 1
µg of oligo(dT)12–18 and avian myeloma virus
reverse transcriptase at 37°C for 4 h. Reagents were purchased
from Promega (Madison, WI). RT-PCR was conducted in a volume of 50 µl
with 40 ng of the cDNA product, 2.5 U Taq polymerase
(Boehringer Mannheim, Mannheim, Germany), 1.5 µM each of the specific
upstream and downstream primers, and standard PCR reagents (Life
Technologies) using a Hybaid-Omnigen cycler (Teddington, Middlesex,
U.K.). For chemokine and cytokine amplification, PCR was performed as
follows: initial denaturation for 5 min at 95°C, then 20 cycles of
denaturation for 40 s at 95°C, annealing for 1 min at 62°C,
and extension for 3 min at 72°C. PCR amplification of gp130 and IL-6R
was conducted as follows: initial denaturation for 5 min at 95°C,
then 25 cycles of denaturation for 40 s at 95°C, annealing for 1
min at 55°C, and extension for 3 min at 72°C. Samples lacking cDNA
or RNA served as negative controls. The PCR products were run on 1%
agarose gels in 1 x TBE (Tris-borate-EDTA buffer) and stained
with ethidium bromide. Amplification of a defined IL-6R sequence by the
primers selected was ascertained by a positive signal with HepG2 cells.
Intron-spanning primers were selected, and the primer sequences
used are shown in Table I
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Chemokines or cytokines released by stimulated SMC were
determined by enzyme immunoassay as follows: IL-6 and IL-1 (Medgenix,
Ratingen, Germany), MCP-1, RANTES, macrophage inflammatory protein
(MIP)-1 and MIP-1ß (R&D Biosystems), and IL-8 (Innogenetics,
Zwijndrecht, Belgium).
Chemotaxis assay
Monocyte chemotaxis was evaluated in 48-well microchemotaxis chambers (Nucleopore, Cambridge, U.K.). Supernatants of Hyper-IL-6-treated SMC were assayed in dilutions from 1:1 up to 1:500. As a control, cell-free medium or supernatant dilutions containing anti-MCP-1 Ab (1:200) were used. Supernatants were filled in the lower wells of microchemotaxis chambers that were separated by polycarbonate filters (5 µm pore size) from the upper wells containing 1 x 105 human monocytes in the same medium. After 90 min at 37°C the number of migrated monocytes was determined in five high power fields. The chemotactic index was calculated by dividing the mean number of migrated monocytes in SMC-supernatants by the number of migrated monocytes in medium alone (spontaneous nondirected migration, ± SD).
Immunocytochemical detection of surface gp130 expression
For immunocytochemical analysis, SMC were seeded at 2 x 104 cells/ml on 8-well chamber slides (Nunc, Naperville, IL) and allowed to grow to confluence. After cultivation in the presence of Hyper-IL-6 (10 ng/ml) for 6 or 24 h, SMC were washed twice in TBS, fixed with 18.5% formaldehyde/12.5% glutaraldehyde for 2 h at room temperature, and incubated with the PE-labeled anti-gp130 (1:200) overnight at 4°C. Unstimulated control SMC kept in medium alone were analyzed in parallel. Following repeated washing in TBS, cells were mounted and photographed using a Leitz microscope (Wetzlar, Germany).
Analysis of ICAM-1 and E-selectin expression by cell ELISA
Confluent SMC cultures in 96-well microtiter plates were stimulated with Hyper-IL-6. After the indicated incubation times, cells were washed three times with cold PBS and incubated with FITC-labeled mouse anti-human ICAM-I (1:200) or E-selectin (1:200) for 1 h. An isotype-matched Ab against an irrelevant Ag was used as negative control. After three washes with ice-cold PBS, SMC were lysed with 0.5 N NaOH and the fluorescence intensity was determined in a Fluoroscan.
Proliferation of SMC
SMC were seeded at 2 x 104 cells/ml on 24-well tissue culture plates and allowed to grow for 24 h in the presence of complete medium followed by growth in DMEM without additives for a further 24 h. Then stimulants were added and cultures were pulsed with [3H]thymidine (2–10 µCi/ml; Amersham, Little Chalfont, U.K.) for the final 6 h of incubation. SMC were harvested for analysis of [3H]thymidine incorporation into TCA (5% w/v) precipitable material after 24, 48, or 72 h, respectively. Briefly, cultures were washed with PBS, incubated with ice-cold TCA, solubilized in 0.5 M NaOH, admixed with scintillation fluid (Ready-Safe; Beckman Instruments, Fullerton, CA) and counted in a scintillation counter (Lkb-ß; Beckman Instruments). SMC cultures grown in the presence of 10% human AB serum served as positive proliferation controls. SMC grown in medium alone served as controls of unstimulated proliferation. Each experimental condition was conducted in triplicate.
Detection of cellular toxicity and apoptosis
Cytotoxic effects of Hyper-IL-6 on SMC were determined by quantitating the reduction of intracellular ATP and apoptosis was detected by analysis of DNA fragmentations as well as by a commercially available text kit (Boehringer Mannheim), which detects single and double-stranded DNA breaks that occur at early stages in apoptosis based on TUNEL, as described (34).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Quiescent SMC expressed only scant amounts of gp130 mRNA. However,
treatment of the cells with Hyper-IL-6 led to induction of the
mRNA-encoding gp130, which became detectable after 4 h, peaked at
48 h, and disappeared after 72 h of stimulation (Fig. 1A). Similarly, IL-6 and
sIL-6R induced gp130 mRNA after 24 h of stimulation (Fig. 1B). Treatment of SMC with IL-6 or sIL-6R alone had no
effect (data not shown). In contrast to gp130, mRNA encoding the IL-6R
was never detected in SMC following simultaneous stimulation with IL-6
and sIL-6R or with the fusion protein Hyper-IL-6.
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). The staining revealed a weak basal
surface expression of gp130 on unstimulated SMC (Fig. 2A),
which was greatly enhanced in the presence of the IL-6/sIL-6R fusion
protein (10 ng/ml) after 8 h (Fig. 2B). Gp130 surface
expression was further intensified after 20 h of stimulation (Fig. 1
C). Experiments were also conducted using a combination of
purified recombinant IL-6 and sIL-6R. Combinations of 250 ng/ml IL-6
plus 750 ng/ml IL-6R were found to elicit similar effects as evoked by
Hyper-IL-6 (data not shown). These results identified SMC as the first
example of cells in which expression of gp130 is subject to massive
up-regulation by the IL-6/sIL-6R complex.
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Treatment of SMC with IL-6 alone led to a very weak induction of
IL-6 mRNA (Fig. 3A).
Similarly, the sIL-6R alone presumably together with endogeneously
produced IL-6 (35) induced only faint expression of IL-6
mRNA after 24 h of stimulation (Fig. 3B). In contrast,
simultaneous stimulation with IL-6 and sIL-6R resulted in a marked,
dose-dependent expression of IL-6 mRNA (Fig. 3C). Hyper-IL-6
provoked an even more pronounced and sustained induction (Fig. 3D). Expression of IL-6 mRNA commenced after 8 h,
peaked at 24 h, and remained elevated over 72 h (Fig. 3D). IL-6 mRNA expression was accompanied by the release of
IL-6 (Table II). These results revealed
that the IL-6/sIL-6R triggers an autocrine amplification loop in
SMC.
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The kinetics of MCP-1 mRNA expression by human vascular SMC are
shown in Fig. 4. Treatment with
Hyper-IL-6 stimulated MCP-1 mRNA expression (Fig. 4A). MCP-1
mRNA peaked between 24 and 48 h, was still detectable after
72 h, and declined to control levels thereafter. When cells were
stimulated with the combination of IL-6 and sIL-6R, a comparable
selective induction of MCP-1 expression ensued (Fig. 4B).
MCP-1 mRNA was undetectable in control cells. Treatment of SMC with
IL-6 or sIL-6R alone did not result in detectable MCP-1 mRNA expression
(data not shown). Expression of mRNAs coding for the chemokines IL-8,
RANTES, MIP-1, or MIP-1ß were not detected (data not shown).
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). However, when SMC were incubated with the
combination of recombinant IL-6 and the sIL-6R and even more so with
Hyper-IL-6, high levels of MCP-1 were found in the supernatant. MCP-1
induction was selective, and other major chemokines IL-8, RANTES,
MIP-1, and MIP-1ß were not detected (Table II). Secreted MCP-1 was
biologically active as demonstrated in chemotaxis assays (Fig. 5). Dilution experiments yielded a
typical bell-shaped dose-response curve with a maximal chemotactic
index of 3.3 at 10 ng/ml MCP-1. Specificity was confirmed by the use of
a neutralizing anti-MCP-1 Ab, which caused marked reduction in
chemotactic activity of the cell supernatants (Fig. 5).
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Cultivation of SMC in the presence of either IL-6 or sIL-6R alone
had no effect on ICAM-1 or E-selectin expression after 6 h
incubation. However, when SMC were stimulated with Hyper-IL-6, a
dose-dependent ICAM-1 expression was induced (Fig. 6A). Maximal induction of
ICAM-1 expression was observed at 5 ng/ml Hyper-IL-6. A comparable
expression of ICAM-1 was observed after treatment of the cells with the
IL-6/sIL-6R complex (Fig. 6B). At all concentrations tested,
Hyper-IL-6 (Fig. 6C) or the natural IL-6/sIL-6R complex
(data not shown) had no effect on E-selectin expression on these
cells.
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Hyper-IL-6 dose-dependently induced proliferation of SMC (Fig. 7A). Results are given for
three different isolates of human primary vascular SMC. The
proliferative response to IL-6/sIL-6R fusion protein displayed
individual variation, but the dose-response curves were similar. Over
time, Hyper-IL-6-induced proliferation increased substantially. As
exemplified for SMC16, proliferation kinetics conducted with 10 ng/ml
Hyper-IL-6 are shown in Fig. 7B. After 72 h of
incubation, Hyper-IL-6 resulted in a 6-fold increase in
[3H]thymidine incorporation, which was
reflected by a proportional increase in cell number. Stimulation of the
cells with the combination of IL-6 and sIL-6R also induced cell
proliferation but to a lesser extent compared with Hyper-IL-6 (Fig. 7, C and D). It is of note that the effects of the
IL-6/sIL-6R complex as well as of Hyper-IL-6 become much more
pronounced with prolonged time of incubation. At the concentrations
tested, Hyper-IL-6 did not induce cytotoxic effects or apoptosis, as
determined by measurements of intracellular ATP and by the absence of
DNA fragmentations and negative TUNEL stainings (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Activation of SMC by the IL-6/sIL-6R system provokes a spectrum of
proinflammatory responses. Further to induction of IL-6, massive
secretion of MCP-1 occurs. Induction of this chemokine was surprisingly
selective, and increases in IL-8, RANTES, MIP-1, and MIP-1ß were
not noted. Induction of MCP-1 conceivably provides a mechanism for
selective recruitment of monocytes and T lymphocytes from the
circulation to the site of inflammation (40, 41, 42, 43).
Furthermore, MCP-1 may induce migration of SMC to the lesion
(44). Creation of the putative IL-6 autocrine
amplification loop is conceptually analogous to the autocrine/paracrine
effects of IL-1 on SMC (24). However, unlike IL-6, IL-1
remains cell-associated, so its effects on SMC may be more locally
restricted.
Another consequence of SMC activation by IL-6/sIL-6R was the
up-regulation of ICAM-1 expression, similar to that observed after
treatment with other inflammatory cytokines such as TNF-
(22) or with enzymatically modified LDL (45).
In the context of cell adhesion, MCP-1 may fulfill a dual role, because
chemokine stimulation leads to strengthening of interactions between
cell adhesion molecules (46). It is noteworthy that
enhanced ICAM-1 expression was not observed in a previous study that
investigated the effects of IL-6 on rat SMC, which is now
explained by the finding that IL-6 cannot act on the cells in the
absence of sIL-6R (22).
Of particular interest is the finding that the IL-6/sIL-6R autocrine stimulation loop induces proliferation of SMC, which is a hallmark of chronic vascular inflammation (15, 16). Previous reports have linked SMC proliferation to the action of PDGF, FGF-ß, or IL-1 (17, 18, 19, 20, 25, 26, 27, 47, 48, 49). Now, IL-6/sIL-6R can be added to the list. It is known that serum levels of sIL-6R may attain levels well above 150 ng/ml (50) while those of IL-6 may surpass 1500 ng/ml (51), so that even higher tissue levels may be anticipated. In early accelerated atherosclerosis (52) and arteriosclerotic obliterance (53), high levels of serum IL-6 correlate with disease progression. Thus, the in vitro data obtained are within realistic levels. Notably, the one primary SMC culture established from a young, 25-year-old patient responded with a higher proliferation rate to Hyper-IL-6 compared with those cultures derived from aortas of elderly patients. The simplicity of the IL-6/sIL-6R system is especially appealing in situations where inflammation is initiated in the paucity of cellular infiltrates. Atherogenesis may represent an important example. Here, blood monocytes are attracted to LDL deposits, and the uptake of degraded LDL then leads to IL-6 secretion and to shedding of sIL-6R. Studies are underway to determine whether these events alone might suffice to trigger SMC activation and proliferation. The described SMC activation mechanism is possibly operative in other inflammatory afflictions of the vascular system including vasculitis and transplant rejection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mariam Klouche, Institute of Medical Microbiology, University of Mainz, Hochhaus am Augustusplatz, 55101 Mainz, Germany. E-mail address:
3 Abbreviations used in this paper: sIL-6R, soluble IL-6R; SMC, smooth muscle cell; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; LDL, low-density lipoprotein.
Received for publication February 8, 1999. Accepted for publication August 2, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but not by PPAR
activators. Nature 393:790.[Medline]
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