Published online before print November 17, 2005, doi: 10.1161/01.ATV.0000196544.73761.82
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© 2006 American Heart Association, Inc.
Vascular Biology |
Interleukin-18 and Macrophage Migration Inhibitory Factor Are Associated With Increased Carotid Intima–Media Thickening
From Cardiovascular Research Institute and Department of Medicine (V.A.K., B.C.B.) and Functional Genomics Center (A.B.), University of Rochester, NY; Molecular Endocrinology Laboratory (T.A.N., V.A.T.), Institute of Experimental Cardiology, Russian Cardiology Research and Production Center, Moscow, Russia; and Moscow State University (V.A.T.), Moscow, Russia.
Correspondence to Bradford C. Berk, University of Rochester, Box MED 601 Elmwood Ave, Rochester, NY 14642. E-mail Bradford_Berk{at}URMC.rochester.edu
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Abstract |
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Objective— Carotid intima–media thickening (IMT) is a form of vascular remodeling that has a strong genetic component. Recently, we discovered that in response to decreased carotid blood flow SJL mice developed the largest intima among 5 inbred strains. Because the SJL strain is prone to autoimmune diseases, we hypothesized that inflammation contributed to IMT in SJL mice.
Methods and Results— We compared vascular remodeling (induced by 2 weeks of low flow) in 2 strains with small IMT (C3H/HeJ and C3HeB/FeJ) versus 2 strains with large IMT (FVB/NJ and SJL/J). Quantitative immunohistochemistry showed a dramatic increase in inflammatory cells per intima area in SJL compared with other strains. Microarray profiling of inflammatory gene mRNAs from carotids showed significant increases in interleukin (IL)-18 and Mif gene expression in SJL compared with C3HeB/FeJ mice. Increased expression of these genes was confirmed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Furthermore, greater cell proliferation in the intima of SJL accounted for increased intima–media thickening, whereas a higher level of apoptosis and a lower level of proliferation were observed in C3HeB/FeJ mice.
Conclusion— The present study indicates that increased expression of Mif and IL-18 cytokines is associated with intima–media thickening in SJL mice, likely by stimulating inflammation and proliferation.
The role of inflammation was studied in progression of intima–media thickening (IMT) in response to low blood flow in 2 inbred strains of mice. Significantly higher expression of IL-18 and macrophage migratory inhibitor factor proteins was associated with significant differences in IMT between SJL/J and C3HeB/FeJ mice.
Key Words: carotid artery • cytokine • flow • IL-18 • inflammation • intima–media thickening • microarray • Mif • mouse
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Introduction |
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Carotid intima–media thickening (IMT) is a significant predictive factor for future cardiovascular events.1 Although the mechanism for IMT progression is unclear, vascular inflammation is an important mediator of all stages of atherosclerosis.2 Whereas monocytes are important in fatty streak formation, the roles of leukocyte and monocytes in IMT are unknown. An important role for inflammatory cytokines is supported by several transgenic mouse experiments.3–7 In particular, interleukins are considered key agonists for the chronic vascular inflammatory response present in atherosclerosis.
We recently developed a mouse model of IMT induced by low flow8 and found dramatic strain-dependent differences in vascular remodeling among 5 inbred strains of mice.9 Among these strains the SJL strain exhibited the greatest intima formation with reduction of the remodeling index.9 Histology showed large numbers of proliferating cells with basophilic nuclei suggesting inflammation. Immune defects in both C3H/HeJ and SJL mice are well known.10 In SJL mice, natural killer T cells exhibited a different profile of secreted cytokines in response to 
-galactosylceramide compared with C3H/HeJ mice.11 However, C3H/HeJ mice are known for their defective response to lipopolysaccharide (LPS) caused by a mutation in the toll-like receptor 4 (TLR4), whereas the other C3H sub-strains are TLR4-sufficient.12 TLR4 is important for neointima formation13 and outward remodeling.14 Recent data suggest an important interplay between innate immunity and inflammation in atherosclerosis as shown by a cross of TLR4 and MyD88 knockout mice onto an atherosclerotic background.7
In this study we investigated the genetic mechanisms responsible for IMT in response to blood flow reduction. We compared 2 inbred mouse strains—C3HeB/FeJ and SJL/J—to evaluate the mechanisms and mediators of inflammation in IMT progression.
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Methods |
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Animals
Male and female C3H/HeJ (C3H/H), C3HeB/FeJ (C3H/F), FVB/NJ (FVB), and SJL/J (SJL) mice (8 weeks old; Jackson Laboratories, Bar Harbor, Me) were used in accordance with the guidelines of the National Institutes of Health and American Heart Association for the Care and Use of Laboratory Animals. All procedures were approved by the University of Rochester Animal Care Committee.
Surgery and Immunohistochemistry
Mice were anesthetized with a cocktail of ketamine and xylazine and maintained at 37°C as described.8 Blood flow in the left common carotid artery was reduced by partial ligation of the left external and internal carotid arterial branches. The branches of the left carotid artery were exposed, but not ligated (sham operation). In the first experiment, 2 groups of ligated or sham-operated animals of each strain were processed for morphological and immunohistochemical studies at 14 days after the surgery. Animals were perfusion-fixed, carotids were harvested and embedded in paraffin, and cross-sections (4 µm) were made as described,8 stained with hematoxylin and eosin, and analyzed using MCID image software (Imaging Research Inc, St. Catharines, Canada). Vessel compartment volumes were calculated as previously described.9 Selected samples (600 to 1000 µm from carotid bifurcation) from inbred strains (2 to 3 shams, 3 to 5 ligated) were evaluated using Ki-67 (1:500; DAKO), 1-actin (1:1000; DAKO), CD45 (1:100; Pharmingen), caspase-3 (1:4000; Serotec), IL-18 (1:3000; Torrey Pines Biolabs), and Mif antibody (1:500; Santa Cruz) as reported.8
Microarray and Quantitative Reverse-Transcription Polymerase Chain Reaction
In the second experiment, 2 groups of ligated or sham-operated animals (C3H/F and SJL mice) were processed for microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) studies at 14 days after the surgery. Mouse carotids were harvested and frozen in liquid nitrogen (LN2) for total RNA isolation using Qiagen RNAeasy Micro kit. RNA integrity was examined by Agilent 2100 Bioanalyser using RNA6000 NanoAssay (Agilent Technol). Ambion MessageAmp aRNA kit was used for RNA amplification and biotinylation with biotin 11-CTP and biotin 16-UTP mixture (Perkin Elmer) for microarray analysis. After amplification, 5 µg of aRNA of each sample was used for Oligo GEArray Mouse Common Cytokines Microarray (OMM-21; SuperArray) hybridization, followed by fluorescent detection using Chemiluminescent Detection Kit (SuperArray) and Cy5-Streptavidin (Amersham Pharmacia Biotech). The arrays were scanned using a Scan Array Lite Microarray Scanner (Perkin Elmer). The online GEArray software was used for image processing and intensity data extraction. Quantitative RT-PCR analyses were performed using ABI Prism 7900HT sequence detection system (Applied Biosystems). Double-stranded cDNA template preparation and purification were performed with Ambion MessageAmp aRNA kit. The qPCR primers and Master Mix from RT2 Real-Time Gene Expression Assay kits (SuperArray) were obtained for 3 mouse genes: GADPH (QPM02946A), IL-18 (QPM03112A), and Mif (QPM02985A). Each reaction contained 2 µL of SYBR Green PCR Master Mix (Applied Biosystems) and 2 µL diluted cDNA (1:100). The PCR consisted of an initial enzyme activation step at 95°C for 15 minutes, followed by 40 cycles of 95°C for 30 sec, 55°C for 30 sec, and 72°C for 30 sec.
Statistics
All results are reported as mean±SEM. Statistical tests were performed with STATVIEW for MacIntosh, version 5.0.1. Comparisons were made by t test or ANOVA for repeated measures, as appropriate. The level of P<0.05 was regarded as significant.
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Results |
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Morphometry of the Left Carotids
We recently reported significant strain-dependent differences in vascular remodeling among 5 inbred strains of mice.9 Figure 1 provides morphometric analysis of left carotids from SJL, FVB, and 2 C3H inbred substrains (C3H/H and C3H/F). Changes in physiological parameters were similar between C3H/F and C3H/H substrains of mice (data not shown). A similar response to ligation in C3H/F compared with C3H/H was observed (Figure 1A versus 1B; Figures I and II, available online at http://atvb.ahajournals.org). As previously reported, intima formation was greatest in FVB and SJL (Figure 1C and 1D). Morphometric analysis of left carotid compartments after ligation is shown in Figure 1E to 1H. Lumen diameter significantly decreased after ligation in both C3H/F and C3H/H to a similar extent. There was also a small decrease in lumen in SJL mice. In contrast, FVB exhibited an increase in lumen (Figure 1E). The biggest media response occurred in FVB (
3-fold increase), with increases of 2-fold in SJL, whereas no changes were found in both C3H substrains compared with shams (Figure 1F). No intima formation was detected in the sham carotids after surgery (Figure 1G). Similar to the media, the greatest intima formed in SJL and FVB, whereas very little intima was seen in C3H strains (Figure 1G). The adventitia also increased in FVB and SJL compared with shams, but was unchanged in both C3H strains (Figure 1H). In summary, there were no statistically significant differences between C3H/H and C3H/F mice in the remodeling response, whereas both SJL and FVB exhibited significant increases in intima and media in response to low flow.
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P<0.05 compared with FVB; #P<0.05 compared with SJL; 
P<0.05 compared with C3H (ANOVA).
Quantitative Immunohistochemistry
To gain insight into mechanisms for these morphological differences between inbred strains of mice, we evaluated cell composition in the remodeled carotids (Figure 2). We performed immunohistochemistry without counterstaining, followed by quantitative analysis using MCID image software, similar to that reported by Phillips et al.15 Representative photomicrographs of CD45+ and smooth muscle 1-actin–positive staining are shown in Figure 2A and 2B. Insets show the strains with the least immunoreactivity as a guide to background staining (for CD45, C3H/F; and for 1-actin, SJL [open arrows]; Figure 2A to 2B). Quantitative analysis was performed for immunoreactive cells normalized to the specified vessel compartment area. In sham-operated animals, quantitative evaluation of CD45 showed no staining within the media area and very little staining in the adventitia (Figure 2C and 2E). The biggest difference in CD45+ cells among the inbred strains was the dramatic increase in the intima–media of SJL mice after ligation (Figure 2C). SJL mice also exhibited a significant decrease in smooth muscle 1-actin expression, compared with the other strains (Figure 2D). CD45+ cells also increased in the adventitia of SJL, but significantly decreased in FVB, and did not change in C3H mice (Figure 2E). FVB mice showed significantly increased 1-actin expression in adventitia compared with shams or other mice strains (Figure 2F). In summary, SJL mice showed dramatically increased expression of inflammatory cells (in intima, media, and adventitia) coupled with decreased vascular smooth muscle cell (VSMC), whereas FVB showed increased VSMC. There were minimal alterations in C3H mice as expected because they had no intima.
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Microarray Profiling
We chose C3H/F and SJL strains for subsequent analyses because they showed the greatest difference in intima formation (Figure 1G) and CD45+ cells (Figure 2C). To identify specific pathways responsible for increased inflammation in SJL, we compared cytokine mRNA expression in C3H/F and SJL 2 weeks after ligation using a commercially available microarray. Among 121 well-known cytokines (Table I, available online at http://atvb.ahajournals.org), Mif mRNA was the only mRNA more highly expressed in the left carotid artery (LCA) from sham SJL compared with sham C3H/F (Table). The only cytokine that exhibited increased expression in SJL ligated LCA compared with sham LCA was IL-18, whereas no differences were observed in C3H/F ligated LCA compared with sham (Table). Of greatest interest, comparison of microarrays from ligated carotids of C3H/F and SJL mice showed that Mif and IL-18 expression were significantly increased in SJL compared with C3H/F (Table). However, expression of GAPDH was similar on all membranes (Table). Thus, based on our cytokine gene analyses we found that Mif differed between SJL and C3H/F initially, and increased expression of IL-18 and Mif was associated with increased carotid intima–media thickening in SJL.
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Confirmation of Microarray Data
In a separate experiment we validated our microarray data using the same samples of aRNA from the carotid arteries. We confirmed cytokine expression differences between experimental groups for Mif and IL-18 by qRT-PCR (Table). In addition, we evaluated carotids for Mif and IL-18 expression by immunohistochemistry (Figure 3). In sham carotids, Mif expression was similar in the media of both strains, although there was more Mif staining in endothelium and adventitia of SJL (compare Figure 3A and 3B). Ligated LCA from SJL exhibited significantly more Mif than C3H/F, especially in the intima, consistent with the microarray results (Figure 3C versus 3D). There were no differences in IL-18 expression in the LCA from sham operated animals of both inbred strains (insets, Figure 3E and 3F). However, SJL expression of IL-18 was significantly greater than C3H/F mice, especially in the intima, consistent with microarray results (Figure 3E versus 3F).
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Cell Turnover Within Remodeled Carotids
To define further mechanisms by which inflammatory cytokines regulate intima–media thickening in C3H/F and SJL inbred mouse strains, we evaluated cell proliferation and apoptosis in ligated LCAs (Figure III, available online at http://atvb.ahajournals.org; Figure 4). There was no cell proliferation (measured by Ki-67) in the LCA from sham operated animals of both strains (data not shown) as we previously observed in C57Bl/6J mice.8 After ligation SJL mice showed a significant increase in proliferation in the intima (white arrows, Figure IIIA) compared with C3H/F (Figure IIIB). By quantitation of the total cell number per field there was a significantly increased in cell proliferation in the intima of SJL compared with C3H/F (Figure 4). When adjusted by vessel area differences in proliferation rate were more pronounced, perhaps because of the significant decrease in vessel wall in C3H/F (Figure IIIE). In contrast to the Ki-67 data, expression of caspase-3 was significantly increased in the intima in C3H/F compared with SJL (gray bars, Figure 4; Figure IIIF). Taken together, these data suggest that the rate of cell turnover in the carotid artery dramatically differs between SJL and C3H/F mice. As predicted, a higher proliferation was associated with IMT in SJL, whereas significantly greater apoptosis was associated with decreased IMT in C3H/F.
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Discussion |
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The major finding of the present study is that expression of the inflammatory cytokines IL-18 and Mif was associated with increased carotid IMT in SJL compared with C3H/F inbred mice in response to a reduction in blood flow. We recently showed that vascular remodeling differed significantly among 5 inbred strains of mice with the greatest difference in intima formation between C3H/H and SJL mice.9 In the present study we compared 2 C3H substrains (C3H/H and C3H/F) and did not found any morphological differences in remodeling in low flow carotids (Figure 1; Figures I and II). Quantitative immunohistochemical evaluation of carotids after ligation showed a dramatic increase in inflammatory cells in the intima of SJL compared with other strains (Figure 2). The increased inflammation in SJL mice appeared to be mediated, in part, by Mif and IL-18 cytokines based on microarray, qRT-PCR and immunohistochemistry (Table; Figure 3). Although the fold-increase in IL-18 and MIF mRNA expression was small (especially when compared with the immunohistochemistry), we believe that this nevertheless partially explains the significant differences in leukocyte accumulation. One possible explanation is that the mRNA data reflect a single time point, whereas the immunohistochemistry represents accumulation of proteins over the 2 weeks. Alternatively, it is possible that at early time points mRNA levels were higher. In addition, we showed significant differences in cell growth and apoptosis that likely contributed to IMT. Specifically there was increased proliferation in SJL and increased apoptosis in C3H/F mice (Figure 4), which may explain the decreased intima in C3H/F compared with SJL mice (Figure 1).
Using a cytokine specific microarray we found significant increases in IL-18 and Mif gene expression in SJL compared with C3H/F mice that were confirmed by qRT-PCR and immunohistochemistry. These data suggest that inflammation plays a significant role in progression of IMT in response to low flow. A potential mechanism could be increased monocyte recruitment (and retention) to the low flow carotid caused by Mif expression by endothelial cells. The monocytes now secrete IL-18, which drives further inflammation and Mif expression, creating a chronic inflammatory response. A recent publication16 showed a strong correlation between serum levels of IL-18 and carotid IMT in patients, and the AtheroGene study17 identified an IL-18 polymorphism that associated with cardiovascular disease. Also, IL-18 has been shown to increase VSMC growth.18
Of interest, the SJL and C3H inbred strains of mice are well-known for their impaired immune responses because of a defect in B cells in C3H/H, whereas both T and B cells are defective in SJL.10 Flow-induced vascular remodeling requires involvement of several cell types (endothelial, smooth muscle, blood-derived mononuclear, and progenitors), but in the present study monocyte/macrophages were most apparent in remodeled carotids only from SJL mice (Figure 2). Proinflammatory cytokines (eg, IFN-
, MCP-1, IL-6, IL-18, and IL-12) have been shown to affect atherosclerosis progression, possibly via innate immune responses involving Toll receptors.3–6,19 C3H/H mice are known for their defective response to LPS due to a mutation in TLR4, whereas the C3H/F is TLR4-sufficient.12 Our data suggest that alterations in TLR4 signaling do not account for differences in intima formation, despite experimental evidence that TLR4 is important for neointima formation,13 and outward remodeling,14 because C3H/H and C3H/F mice have the same remodeling response after flow reduction (Figure 1; Figures I and II). Thus, whereas TLR4 and its downstream adaptor molecule MyD88 appear to be important in atherosclerosis in a hypercholesterolemic mouse model, there does not appear to be a role for TLR4 in flow induced remodeling.7 Instead, we believe that there is a difference in secretion of proinflammatory cytokines in response to low flow. For example, focal cerebral ischemia significantly increased microglial–macrophage synthesis of tumor necrosis factor- in SJL mice.20 Taken together, our data suggest that IMT in SJL mice after flow reduction depends on inflammatory cytokine expression within the vessel wall.
The major finding of our study was the pathophysiological upregulation of IL-18 and Mif in carotids from SJL compared with C3H/F mice (Table). IL-18 belongs to the IL-1 cytokine family and is also known as IFN- inducing factor.21 A proatherogenic role for IL-18 was recently suggested based on animal experiments, human epidemiology, and clinical trials.5,16,17,22–25 In patients with cardiovascular disease, the serum concentration of IL-18 was a strong predictor for cardiovascular death,23 probably because of the adverse effect of IL-18 on plaque stability.5 Our recent data showed that patients with acute coronary syndromes had a significantly higher serum level of IL-18 and unopposed IL-18 activity caused by lower IL-18 binding protein.25 Plasma IL-18 is an independent risk factor for hyperhomocystinemia and IMT in patients with type 2 diabetes.24 Two recent epidemiological studies suggested a causative role of IL-18 in atherosclerosis.16,17 High plasma IL-18 was predictive for an increased IMT in humans,16 and polymorphism of the IL-18 gene significantly affected circulating levels of IL-18 and clinical outcome in patients with coronary artery disease.17 IL-18 is found in macrophages in atherosclerotic plaques in human carotids.5 It was proposed that endothelial cells and monocytes/macrophages, but not VSMC, are targets for IL-18, based on expression of the IL-18 receptor.5,26 However, a recent publication showed that IL-18 stimulated rat aortic smooth muscle cell proliferation via increased transcription of chemokine CXCL16.18 Consistent with a key role for IL-18, SJL mice exhibited increased inflammatory cell content in the intima–media (Figure 2) associated with expression of IL-18 (Table; Figure 3E). Our data on the pathological role of IL-18 in SJL mice are consistent with previous observations that LPS-stimulated macrophages from SJL mice produced IL-18.27 However, the IL-18–dependent pathway(s) responsible for IMT require further investigation, because IL-18 can accelerate atherosclerosis even in the absence of activated T cells.28
We found that Mif mRNA expression was greater in carotids from SJL than C3H/F both at baseline and after flow reduction (Table). In particular, we observed increased Mif-positive cells in the adventitia and endothelium of sham-operated SJL compared with C3H/F mice, although expression in media was the same (Figure 3A and 3B). This finding may be consistent with the concept that some vessels are "primed" for inflammation such as SJL carotids. Importantly, microarray analysis of ligated SJL carotids showed a significant increase in Mif expression that may contribute to the differences in remodeling between SJL and C3H/F (Table; Figure 3C and 3D). In contrast to cytokines that are induced by inflammation (eg, IL-18), Mif is constitutively expressed in many tissues.29 Of interest, a recent study showed coinduction of IL-18 and Mif during retinoic acid-induced differentiation of embryonic stem cells,30 suggesting that they may share a signaling pathway. De novo Mif expression was reported previously in endothelial cells and macrophages in a rabbit atherogenesis model,31 as well as in human atherosclerosis.32 Most relevant to our findings is a recent report33 that inhibiting Mif (monoclonal antibody injections) reduced macrophage number and increased VSMC number in wire-injured apolipoprotein E–/– mice carotids.
There are 2 major limitations of our study: (1) a limited number of cytokines (121 gene) being evaluated and (2) because gene expression was investigated at only a single time point, our data do not obviate the possibility of cytokines other than IL-18 and MIF being present at different times during arterial remodeling.
In conclusion, our data suggest that the inflammatory response to a chronic reduction in blood flow is genetically determined and plays an important role in IMT. Consistent with clinical observations,5,16,17,22–25 our findings suggest a critical role for increased IL-18 and Mif expression in flow-dependent IMT progression, likely via recruitment of monocytes, retention of macrophages, and subsequent effects on cell growth and apoptosis.
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-62836 to B.C.B. and by National Heart, Lung, and Blood Institute funds for exchanges of scientists under the auspices of the US–Russia Joint Agreement in Cardiopulmonary Research. We thank Mary Georger for helpful suggestions in performing immunohistochemistry. We thank Dr Gwenaele Garin for thoughtful discussion of data.
Received June 6, 2005; accepted November 3, 2005.
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