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Annals of Clinical & Laboratory Science 36:179-184 (2006)
© 2006 Association of Clinical Scientists

Murine Cytomegalovirus Infection Markedly Reduces Serum MCP-1 Levels in MCP-1 Transgenic Mice

M. Kent Froberg1, Devon Dannen1, Alice Adams1, Jan Parker-Thornburg2 and Pappachan Kolattukudy3
1 Department of Pathology, University of Minnesota Duluth School of Medicine, Duluth, Minnesota2 Genetically Engineered Mouse Facility, MD Anderson Cancer Center, Houston, Texas3 Burnett College of Biomedical Sciences, University of Central Florida, Orlando, Florida

Address correspondence to M. Kent Froberg, M.D., Department of Pathology, School of Medicine, University of Minnesota Duluth, 1035 University Drive, Duluth, MN 58812, USA; tel 218 726 7223; fax 218 726 7559; e-mail kfroberg{at}d.umn.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Monocyte chemoattractant protein-1 (MCP-1) is a pro-inflammatory chemokine believed to play a major role in atherogenesis. Injured endothelial cells express MCP-1, which attracts monocytes to the blood vessel wall and leads to the formation of atheromas. Cytomegalovirus infection may also play a role in atherogenesis and accelerates inflammation in tissues that overexpress MCP-1. To examine the relationship of cytomegalovirus infection and MCP-1, we infected MCP-1 transgenic mice with murine cytomegalovirus (MCMV) and collected serum 6 days post-infection to evaluate TH1-related cytokine levels by ELISA. Serum levels of IL-10, IL-12 and IFN-{gamma} were increased in MCP-1 transgenic mice on day 6 following MCMV infection, while levels of IL-1ß and TNF-{alpha} were undetectable. However, MCP-1 serum levels were reduced >50% in MCP-1 transgenic mice following MCMV infection compared to uninfected transgenic mice. This effect was not as dramatic when an M33 null MCMV was administered to MCP-1 transgenic mice. The mechanism by which MCMV lowers serum MCP-1 levels is unknown, but this effect may enhance the survival of the virus and thus allow CMV to contribute to the chronic inflammation of atherogenesis.

Keywords: cytomegalovirus, atherosclerosis, monocyte chemoattractant protein-1, cytokines


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Atherosclerosis is the major cause of cardiovascular disease in the United States and can lead to long-term sequelae such as myocardial infarction, stroke, or gangrene. Major risk factors for atherosclerosis include hypertension, diabetes, cigarette smoking, and hyperlipidemia. Cytomegalovirus (CMV) infection may contribute to atherogenesis through endothelial injury or activation of pro-inflammatory cytokines and growth factors involved in atherogenesis [1]. Following endothelial injury, MCP-1 secretion attracts monocytes, which enter the vessel intimal layer and become activated macrophages expressing scavenger receptors that bind and take up oxidized LDL cholesterol to become foam cells. Chronic or episodic inflammatory damage to the vessel wall leads to atheroma formation with narrowing of the arterial lumen ultimately leading to a pro-thrombogenic environment. CMV is a risk factor for restenosis following angioplasty and de novo atherosclerosis following heart transplantation [2,3]. CMV DNA is commonly present in atheromatous vessel walls and can initiate inflammatory changes that may accelerate atherogenesis [4]. The host response to CMV infection is similar in many ways to the fibro-inflammatory pathway leading to advanced atherosclerosis. During CMV infection, the virus appears to initiate and upregulate many pro-inflammatory substances followed by down-regulation of these same cytokines and chemokines, thus enhancing virus spread, multiplication, and long-term survival.

MCP-1 appears to play a pivotal role in the initial and episodic inflammatory events of atherogenesis. MCP-1 mRNA is overexpressed in atherosclerotic lesions in humans compared with sections of arteries not exhibiting atherosclerotic changes [5]. In apo-lipoprotein E (apoE) knockout mice, anti-MCP-1 gene therapy limits the progression and destabilization of preformed atherosclerotic lesions [6]. In co-cultures of human aortic endothelial and smooth muscle cells, LDL in the culture media caused a 7-fold increase in MCP-1 expression with subsequent monocyte migration, which could be blocked by the addition of antibodies to MCP-1 [7]. LDL receptor-deficient mice have high serum cholesterol levels and develop severe atherosclerotic lesions, but when LDL/MCP-1 knockout mice are produced the area of atherosclerotic lesions is reduced by >80% compared to LDL knockouts alone [8]. Additionally, MCP-1 over-expression accelerates atherogenesis in apoE deficient mice [9]. Mice deficient for both apoE and CCR2, the primary receptor for MCP-1, show markedly reduced atheromatous lesions when compared to apoE knockouts alone [10].

We previously demonstrated that inflammation is accelerated in tissues overexpressing MCP-1 in transgenic mice after MCMV infection, compared to wild type mice of the same strain [11]. Since the responses to virus infection and atherogenesis both involve largely TH1-related responses and MCP-1 activity, we determined serum levels of IFN-{gamma}, IL-12, TNF-{alpha}, IL-1ß, IL-10, and MCP-1 following acute MCMV infection in MCP-1 transgenic mice and compared the mean levels to those of uninfected mice. The purpose of these studies was to help define how cytomegalovirus infection may contribute to atherogenesis through viral-induced modulation of pro-inflammatory cytokine and chemokine levels.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Thirty-four 2-mo-old homozygous MCP-1 transgenic mice (FVB/N strain) were obtained from one of the authors (PK) with equal numbers of male and female mice. Mice were maintained in separate cages and given food and water ad libitum. Transgenic mice were given 104 plaque-forming units (PFU) of Smith strain wild type MCMV (VR-1399, American Type Tissue Culture, Rockville, MD), mock infection (culture media minus virus), or M33 null MCMV by ip injection. M33 is a G protein-coupled receptor homolog found in MCMV. US28, found in human CMV (HCMV), is a G protein-coupled receptor homolog that binds MCP-1 with high affinity and may help sequester MCP-1 to escape host immune responses [12]. US28 and M33 gene products mediate smooth muscle migration (a facet of atherogenesis) in vitro [13,14]. When gene transcription is blocked for either US28 or M33, the ability to mediate smooth muscle cell migration is lost. M33 null MCMV (kindly provided by Dr. Helen Farrell) grows normally in tissue culture, but produces an attenuated infection in mice [15]. M33 null virus was used in our study to determine if it interacted with MCP-1 in a manner similar to US28. Virus was grown in SC-1 cells (CRL-1404, ATTC), a cell line of fetal mouse embryo origin, in minimal essential media with Earle’s salts and 1-glutamine (Gibco, Rockville, MD) supplemented with 5% calf serum (Sigma, St. Louis, MO), 100 IU/ml penicillin, and 100 µg/ml streptomycin. For virus production, confluent layers of SC-1 cells were infected with MCMV at a multiplicity of infection of 0.1, and the virus-containing supernatants were harvested 4 or 5 days later. Confluent layers of SC-1 cells in individual wells of 24-well titer plates were used to quantitate virus by plaque assay for subsequent mouse injections. Treated mice received either 104 PFU of wild type or M33 deleted MCMV virus particles in 1 ml of phosphate buffered saline. Mock-infected mice were given an equivalent amount of culture media in 1 ml of PBS to ensure that culture media alone did not alter cytokine levels. One group of transgenic mice was untreated. All mice were euthanized 6 days post-injection and serum was collected and frozen at –70°C until assays were performed. Serum levels for MCP-1, IFN-{gamma} , IL-12, IL-10, IL-1ß and TNF-{alpha} were determined by enzyme-linked immunosorbent assay (ELISA) using a standard kit and the manufacturer’s protocol (Pierce, Rockford, IL). For MCP-1 appropriate dilution levels were established prior to performing ELISA. Samples were run in duplicate in 96 well plates on a plate reader (Molecular Devices, Sunnyvale, CA) to determine absorbance at 450 and 550 nm and mean values compared between treatment and control groups and between treatment groups using the t-test and p ≤0.05 level of significance. Each sample consisted of pooled serum from one male and one female mouse.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mean serum levels of IL-10, IL-12, IFN-{gamma} and MCP-1 are shown in Fig. 1Go. Since no statistical differences in cytokine levels were seen between mock and untreated control groups, or when comparing treatment groups against mock or untreated groups (with the exception of IL-12), all statistical comparisons shown are between the treated and the mock injected group. MCP-1 levels were >60,000 pg/ml in both untreated and mock treated control mice on serum collected on day 6 post-injection. M33 deleted and wild type MCMV injected MCP-1 transgenic mice had a >50% reduction in MCP-1 on day 6 post-injection compared to mock infected mice and these differences were statistically significant, but the difference between the M33 deleted and wild type MCMV infected mice did not reach statistical significance (p = 0.273). Mean IFN-{gamma} serum levels from day 6 post-injection were significantly elevated in both wild type and M33 deleted MCMV treated groups when compared to mock infected mice. While M33 deleted mice had lower total IFN-{gamma} serum levels than wild type MCMV treated mice, this difference did not reach statistical significance (p = 0.060). Serum IL-10 levels were increased on day 6 post-infection for wild type and M33-deleted MCMV treated mice, but statistical significance was reached only for the wild type group (p = 0.002). IL-12 levels were increased over mock-infected mice (p = 0.010), but were decreased compared to controls for the M33 MCMV infected mice (p = 0.027), and the difference between treatment groups was significant (p = 0.004). Serum TNF-{alpha} and IL-1ß were undetectable by ELISA in all treatment and control groups on day 6 post-infection (data not shown).


Figure 1
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  		Fig. 1: ELISA levels (mean ± SE) of MCP-1 (A), IFN-{gamma} (B), IL-10 (C), and IL-12 (D) from serum collected on day 6 post-infection of MCP-1 transgenic mice. Mice either received no treatment (Rx), mock treatment (injection of an equivalent amount of culture media minus virus), M33 null, or Smith strain wild type murine cytomegalovirus (104 PFU) by ip injection. N values consist of serum from one male and one female mouse. (*p <0.05, **p <0.01, ***p <0.001)

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Virus infections are known to cause pro-inflammatory responses and typically involve an increase in TH1-related cytokine levels. These cytokine responses direct cell-mediated host activities that eventually control virus proliferation often leading to clearing of the virus. Cytomegalovirus is known to establish latency followig acute infection and may contribute to the chronic fibro-inflammatory pathway of atherogenesis during the initial infection or during periods of reactivation.

Since MCP-1 appears to play a key role in atherogenesis, we evaluated the cytokine response of MCP-1 transgenic mice to acute MCMV infection. Understanding virus/cytokine interactions could establish how CMV may survive host responses to contribute to atherogenesis. Using ELISA techniques, we demonstrated an increase in serum levels of TH1-related cytokines on day 6 post-MCMV-infection in MCP-1 transgenic mice similar to previously reported serum cytokine levels post-MCMV-infection in other strains of mice. Increased serum levels of IL-12, IL-10 and IFN-{gamma} on day 2 post-MCMV-infection have been reported for C57BL/6, E26 (NK- and T-cell deficient mice) Balb/c, and apoE knockout mice [16–18]. However, to our knowledge there have been no MCMV-related serum cytokine levels reported for FBV/N or MCP-1 transgenic mice. It seems likely that in immunocompotent mice MCMV infection would initially cause a pro-inflammatory response with elevation of serum cytokine levels. However, absolute levels of these cytokines may depend on differences in mouse strain, virus load and strain, testing methodology, and the time period between infection and serum collection. Despite these differences, our data are consistent with previously reported results in mice.

The finding of markedly elevated MCP-1 serum levels in untreated MCP-1 transgenic mice was unexpected and suggests that MCP-1 secretion leads to persistent elevation in MCP-1 in this homozygous mouse model and may help to explain the myocarditis and early mortality previously described [19]. The reduction of serum MCP-1 in M33-deleted and wild type MCMV treated mice was dramatic [Fig. 1AGo] and suggests a mechanism whereby MCMV may initially enhance the host immune response, followed by a rapid diminution of serum MCP-1. Conceivably this would initially allow the influx of monocytes to sites of virus infection. Monocytes may acquire virus particles at this stage of infection and transport them to other tissues, thus increasing CMV dispersal. Subsequent reduction in MCP-1 may ensure virus survival by lowering the monocyte and T-lymphocyte chemo-attractive response at the time of peak viremia. Our study did not address the mechanism of serum MCP-1 reduction by MCMV infection, but a review of the literature related to cytomegalovirus suggests several possible mechanisms. Cytomegalovirus survival within host tissues is likely enhanced by the virus’s ability to subvert host immunosurveillance. HCMV and MCMV are known to produce chemokine receptor homologs that may bind and sequester host chemokines [12]. US28-deleted HCMV mutant-infected cells failed to downregulate extracellular MCP-1 inducing monocyte chemotaxis, while no significant chemotaxis occurred when HCMV infected cells expressing wild type US28 were used, suggesting US28-mediated removal of MCP-1 from the supernatant [20]. This suggests that MCP-1 sequestration by viral products could reduce the chemotaxis of monocytes to virus-infected cells, and provide the virus with a means of avoiding elimination by cell-mediated host responses. Infection of human diploid fibroblasts by HCMV has been shown to initially increase levels of MCP-1 in culture supernatant, followed by a reduction in MCP-1 levels compared to mock infected cells by 48 hr post-infection [21]. This reduction in MCP-1 was not observed when UV–inactivated HCMV was used, indicating MCP-1 downregulation was dependent on the activity of viral genes. Northern blot studies indicated that the reduction of supernatant MCP-1 was secondary to inhibition of MCP-1 at the transcription level. In a similar manner, it is possible that the reduction of serum MCP-1 levels we observed in MCP-1 transgenic mice post-MCMV-infection was due to inhibition of MCP-1 mRNA by virus-encoded genes.

Serum IL-10 levels were increased on day 6 after wild type MCMV infection in MCP-1 transgenic mice [Fig. 1CGo]. IL-10 levels were also higher than controls for mice infected with M33-deleted virus, but this difference did not reach statistical significance [p = 0.240]. Previous studies indicated that IL-10 is upregulated within MCMV-infected macrophages at 24 hr post-infection [22]. This may be especially important because IL-10 levels normally increase late in the host response to infection, are inhibitory to the TH1 pathway, and may, therefore, enhance virus survival. MCMV also produces an IL-10 homolog that may act to further inhibit the host’s cell-mediated response to viral infection [23]. Il-10 inhibits production and release of MCP-1, hence viral induced IL-10 upregulation during early MCMV infection may have contributed to secondary reduction of serum MCP-1 levels in our study [24,25].

We determined that IFN-{gamma} levels were significantly higher than controls on day 6 post-infection [Fig. 1BGo]. IFN-{gamma} is produced by macrophages and NK cells and is known to play an important role in resolution of virus infections. Orange and Biron [16] reported that IFN-{gamma} was increased in serum collected on day 2 after MCMV-infection in C57BL/6 mice, but was not detectable in E26 mice at the same time. E26 mice are NK and T-cell deficient, major sources of IFN-{gamma} . These authors also found serum IL-12 elevated on day 2 post-infection in both C57BL/6 and E26 mice. Furthermore, they reported that in their experiments IFN-{gamma} production by NK cells was IL-12 dependent. Vliegen et al [18] found that plasma IFN-{gamma} levels peaked on day 2 post-MCMV-infection in apoE knockout mice, but were undectable at day 6 post infection. We collected serum only on day 6 post-MCMV infection, but we found IFN-{gamma} statistically increased, compared to controls at that time. The overexpression of MCP-1 in our mouse model may lead to increased levels of activated macrophages and higher levels of serum IFN-{gamma} .

In our studies, IL-12 was significantly elevated following infection with wild type MCMV compared to mock infected mice, while IL-12 was significantly lower in serum of mice infected with M33-deleted MCMV compared to mock-infected mice [Fig. 1DGo]. The difference in serum IL-12 levels between wild type and M33-deleted MCMV treatment groups was also statistically significant [p = 0.004]. This suggests that the M33 gene product may be responsible for IL-12 inhibition in an undetermined manner. These data suggest that MCP-1 transgenic mice have expected TH-1 related cytokine responses following MCMV infection, although these differences are diminished when the M33-deleted virus is used. The exact function of the M33 ORF product remains to be defined, but appears to modify the intensity of host responses to virus infection. In our study, IL-1ß and TNF-{alpha} serum levels were not detectable in any control or treatment groups on day 6 post-infection. Previous studies have documented increases in serum levels of these cytokines within hours following MCMV infection, followed by subsequent decreased cytokine production [16–18]. It seems likely, therefore, that our results are related to the overexpression of MCP-1 as well as the timing of serum collection following MCMV infection.

We found that MCP-1 transgenic mice had very high serum levels of MCP-1 even without MCMV infection, indicating there was constitutive expression of the transgene with leakage from myocardial cells. Despite this, MCMV infected MCP-1 transgenic mice appeared to have anticipated IL-10, IL-12, and IFN-{gamma} responses to MCMV infection. Cytomegalovirus immediate-early genes are known to interact with and activate NF-{kappa} B, which subsequently activates many downstream genes regulating the production of pro-inflammatory cytokines [26]. The finding of reduced serum MCP-1 levels following wild type or M33-deleted MCMV infection was dramatic. We used the M33-deleted MCMV because the HCMV ORF, US28, is a G protein-coupled receptor that has been shown to bind MCP-1 with high affinity, and we hypothesized that M33 may function in a similar manner to sequester MCP-1. While MCP-1 serum levels of M33-null MCMV infected mice were lower than those of mice infected with wild type virus, the difference was not significant, suggesting that the M33 gene product was not responsible for the substantial reduction in serum MCP-1. Further studies are needed to determine if MCMV inhibits MCP-1 at the transcription level, as has been observed in vitro for HCMV.

These studies support the notion that cytomegalovirus initially activates and then inhibits some host pro-inflammatory cytokines and chemokines in vivo. Additional studies could determine if this activity enhances virus survival in host tissues, allowing the virus to accelerate or exacerbate atherogenesis.


   Acknowledgments
 
This study was supported by a Grant-in-Aid from the American Heart Association.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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