EBM Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tomita, M.
Right arrow Articles by Santoro, T. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tomita, M.
Right arrow Articles by Santoro, T. J.
Experimental Biology and Medicine 229:971-976 (2004)
© 2004 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Proinflammatory Cytokine Genes Are Constitutively Overexpressed in the Heart in Experimental Systemic Lupus Erythematosus: A Brief Communication

Michiyo Tomita*,1, Monica Dragoman{dagger}, Heath Worcester{ddagger}, Philip Conran§ and Thomas J. Santoro*,||

* Department of Internal Medicine, University of North Dakota School of Medicine, Fargo, North Dakota 58102; {dagger} Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; {ddagger} Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia 30322; § Medical College of Ohio, Toledo, Ohio 43614; || Research Service, Fargo Veterans Administration Medical Center, Fargo, North Dakota 58102

1To whom requests for reprints should be addressed at 1919 North Elm Street, Fargo, ND 58102. E-mail: mtomita{at}medicine.nodak.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The heart is one of a number of organs that may be affected in systemic lupus erythematosus (SLE), a prototypic autoimmune disease. Potential anatomical sites of involvement include the myocardium, pericardium, endocardium, valves, conduction system and blood vessels that subserve the heart. Typically, the severity of cardiovascular disease in lupus correlates with the degree of systemic inflammation, which is mirrored by the level of C-reactive protein (CRP) in the plasma. C-reactive protein, in turn is regulated by proinflammatory cytokines, such as interleukins (ILs) 1ß and 6. These cytokines have been found in functionally and/or structurally damaged areas of the heart and have been implicated in disease pathogenesis. It has been assumed that the source of these putatively pathogenetically relevant cytokines in the compromised heart is infiltrating mononuclear cells. This study tests the hypothesis that cardiomyocytes per se may contribute to proinflammatory cytokine production in the setting of systemic inflammation. Using as the experimental model MRL/MpJ-Tnfrs6lpr (MRL-lpr/lpr) mice, which spontaneously manifest an autoimmune syndrome that has clinical features of SLE, we show that ventricular homogenates and ventricular cardiomyocytes constitutively overexpress genes encoding the proinflammatory cytokines IL-1ß, IL-6, IL-10, and gamma interferon. The results suggest the possibility that proinflammatory cytokines emanating from the heart may actually contribute to the high levels of CRP that appear to aid in predicting subsequent cardiac events. Viewed in this setting, CRP becomes a footprint of an ongoing pathogenic process mediated, in part, by the heart muscle itself.

Key Words: proinflammatory cytokines • systemic lupus erythematosus • atherosclerosis • coronary heart disease • MRL-lpr/lpr mice • autoimmunity


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE), is a multisystem autoimmune disease of unknown etiology (1–4) accompanied by cardiac involvement in approximately 50% of cases (5). Although all-cause mortality due to SLE-related illness has declined during the last 2 decades, the risk of cardiovascular death in lupus has remained unchanged (6–8). Cardiac involvement in lupus may affect the endocardium, myocardium, pericardium, heart valves, conduction system, and coronary arteries (9, 10). Independent of the site of anatomical involvement or its etiology, inflammation is thought to play a pivotal role in the pathogenesis of cardiovascular disease in SLE (reviewed in 11). Thus, myocarditis, endocarditis, pericarditis, and coronary arteritis typically occur in the setting of highly active lupus (12), and coronary heart disease in SLE is more often observed in patients with poorly controlled disease (13).

Peripheral inflammation is mirrored in part by the production of acute phase reactants such as C-reactive protein (CRP) and serum amyloid A (SAA). Elevated systemic levels of these inflammatory markers (14) are associated with unfavorable prognoses in unstable angina and appear to predict subsequent cardiac events (15–17). The synthesis of both CRP and SAA by hepatocytes is transcriptionally upregulated by proinflammatory cytokines, most notably interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor (TNF) {alpha} (18–22). These and other cytokines have been found in functionally and structurally damaged areas of the heart and have been implicated in disease pathogenesis. The origin of these putative pathogenetically relevant cytokines remains to be fully defined.

In diseases characterized by leukocytic infiltration, such as myocarditis, monocytes, macrophages, and T cells are conventionally thought to account for the spectrum of cytokines found in the heart (23). In atherosclerotic cardiovascular disease, mononuclear cells are also potential sources of cytokine production. Thus, immunohistochemical analysis of atherosclerotic lesions revealed leukocytic infiltrates consisting of ~80% monocytes or monocyte-derived macrophages (M{phi}) and 5%–20% of T cells (24). These M{phi} cells may be recruited to the lesion by interaction with adhesion molecules on endothelial cells and oxidized low-density lipoprotein (LDL) from the fatty core. T-cell clones from atherosclerotic lesions have been shown to produce interferon gamma (IFN{gamma}), and Tellides et al. (25) reported that IFN{gamma} could induce arteriosclerotic changes in the absence of detectable lymphocytes in a posttransplant graft atherosclerosis model using subacute combined immunodeficient (SCID) mice as the host. T-cell clones isolated from atheroclerotic lesions have been shown to recognize oxidized LDL (26) and antigen recognition may be accompanied by cytokine production. Oxidization of LDL by activated macrophages may be enhanced by the TH2 cytokines IL-4 and IL-13 (27), which de Boer et al. (28) have detected in atherogenic plaques. These observations indicate that atherosclerotic lesions may contain mononuclear cell infiltrates, which may produce cytokines and further contribute to the atherogenic process.

On theoretical grounds, cytokine production in the heart may originate not only from infiltrating leukocytes but also from cardiac myocytes. In this connection, multiple cytokine cascades have been shown to be activated within the myocardium in experimental pathological states, such as myocardial infarction (29), and in an experimental model of congestive heart failure, cardiac myocytes from both the atria and ventricle were found to produce leukemia inhibitory factor, a cytokine capable of inducing cardiac hypertophy (30). To explore the possibility that cardiomyocytes may be involved in cytokine production in the setting of inflammation, we examined constitutive gene expression in the hearts of MRL/MpJ-Tnfrs6lpr (MRL-lpr/lpr) mice, a murine model of SLE. MRL-lpr/lpr mice spontaneously develop an autoimmune syndrome characterized clinically by arthritis and immune-complex glomerulonephritis (31), immunologically by deregulated production of cytokines in multiple tissues (32–34), and serologically by autoanti-bodies to Smith antigen and native DNA, which are pathognomonic of human lupus (35). As is true of most inbred mouse strains, MRL-lpr/lpr mice resist atherosclerosis unless given a diet high in saturated fat. Our results indicate that in systemic autoimmunity, the heart, per se, may be a source of proinflammatory cytokines.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Male and female MRL-lpr/lpr (H-2k) and CBA/J (H-2k) mice were purchased from the Jackson Laboratory (Bar Harbor, ME), and maintained in our American Association of Laboratory Animals-approved animal facility. Mice were examined at 6, 20, and 26 weeks of age.

RPMI 1640, Ca2+-free minimal essential medium (MEM), Hanks balanced salt solution (HBSS), Tris-HCl, and agarose were obtained from Gibco BRL (Grand Island, NY). Penicillin/streptomycin and glutamate were purchased from Quality Biological, Inc. (Gaithersburg, MD). dNTPs were obtained from Amersham (Arlington Heights, IL). Fetal calf serum (FCS) was purchased from Hyclone (Logan, UT). [32P]CTP was purchased from NEN (Boston, MA). Taq polymerase was obtained from Promega (Madison, WI). Other chemicals were purchased from Sigma (St Louis, MO). Cytokine primers for reverse transcription–polymerase chain reaction (RT-PCR) were obtained from Biosource International (Camarillo, CA).

For histological analyses, the hearts of 6- and 26-week-old CBA/J and MRL-lpr/lpr mice were fixed with 10% buffered formaldehyde solution and subjected to hematoxylineosin (HE) staining. To detect the presence of fatty streaks oil red O-isopropanol method was employed (36).

Mice were sacrificed by cervical dislocation. The hearts were excised and rinsed in ice-cold Hanks balanced salt solution (HBSS). RNA was isolated from the heart as previously described (37). Five micrograms of RNA were then reverse transcribed using SuperScript reverse transcriptase (Gibco BRL). Polymerase chain reaction was performed on various amounts of 1:50 and 1:150 dilutions of the newly synthesized cDNA from each sample with ß-actin primers for standard curve titration using a modified protocol of Cai et al. (38). Briefly, PCR was performed in a 20-µl reaction mixture consisting of 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 100 µg/ml bovine serum albumin (BSA), 50 µM of each deoxynucleotide triphosphate (dNTP), 250 nM of ß-actin-specific primer, and 1.0 units of Taq DNA polymerase. Following initial denaturation at 94°C for 2 mins, PCR was performed for 30 cycles of denaturation at 94°C for 15 secs, annealing at 60°C for 20 secs, and primer extension at 72°C for 1 min. There followed a final extension at 72°C for 5 mins in order to ensure completion of all reactions. Polymerase chain reaction products were separated on 1.0% agarose gels, and negative images were taken with positive/negative film (Polaroid Corp., Cambridge, MA). Band intensities were obtained using a ScanJet 3c scanner (Hewlett Packard, Palo Alto, CA), and relative values were calculated using the National Institutes of Health Image Analysis 1.58 computer program. Following normalization, PCR was performed using specific primers. Polymerase chain reaction products were separated on a 1.0% agarose gel and, in the case of IL-1ß, IL-6, IL-3, TNF{alpha}, and TGFß1, visualized by ethidium bromide staining. For the cytokines IL-2, IL-10, and IFN{gamma}, gels were further subjected to Southern analyses as described earlier (37, 39) using 30-mer probes. The sequences of primers used in this study have previously been reported (40, 41).

Cardiac myocytes from adult mice were isolated as described by Hilal-Dandan et al. (42) with some modifications. Fifteen minutes after injecting heparin intraperitoneally (10,000 U/Kg; Upjohn, Kalamazoo, MI), the mouse was anesthetized by an intraperitoneal injection of pentobarbital (50 mg/kg). The heart was then excised, rendered free of noncardiac tissues, and cannulated via the aorta. The cannulated heart was transferred to the perfusion setup and perfused (5 ml/min) with Ca2+-free media (MEM without Ca2+ plus 23.8 mM NaHCO3) for 5 mins at 37°C, followed by perfusion for 5 mins with 0.2 mg/ml of collagenase type 2 (>280 µ/mg; Worthington Biochemical Corp., Lakewood, NJ) in Ca2+-free media plus 2% BSA and 10 mM 2,3-butanedione monoxime (BDM; Sigma, St. Louis, MO). Following perfusion, the atria were removed, the ventricles were cut into small pieces then incubated in 3 ml of collagenase solution (same as above) at 37°C for 3 mins in a shaking water bath. Supernatants containing digested cardiac myocytes were collected, and the incubation was repeated 5 to 7 times. The cells were then washed twice and resuspended in Ca2+-free media plus 2% BSA and 10 mM BDM. CaCl2 was then added stepwise from a 1 M stock solution with gentle shaking to provide a final concentration of 1 mM. Cardiac myocytes were considered viable when they had a rod-shaped appearance, clear striations, sharp edges, no evidence of granulation or blebs, and excluded trypan blue dye. The viability of cardiac myocytes was consistently greater than 90% in all preparations reported on. For mRNA extraction, cells were collected by centrifugation and washed twice with Hanks balanced salt solution with Ca2+. The experiment was repeated in three separate sets of mice.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Initially, we compared cytokine gene expression in whole ventricular homogenates from immunologically normal, H-2 identical (H-2K), CBA/J and autoimmune MRL-lpr/lpr mice. mRNA from young (6 weeks old) and old (26 weeks old) mice was reverse transcribed, and cDNAs were amplified by semiquantitative PCR using cytokine primers for IL-1ß, IL-2, IL-3, IL-6, IL-10, IFN{gamma}, TNF{alpha}, and TGFß1. For analyses of IL-2, IL-10, and IFN{gamma}, amplified cDNA was subjected to Southern analyses. The expression of genes encoding the cytokines IL-2, IL-10 and IFN{gamma} was found to be markedly increased in ventricular homogenates of 6-week-old, autoimmune MRL-lpr/lpr mice compared with that in those of age-matched, CBA/J control mice (Fig. 1AGo). The levels of mRNA for IL-2, IL-10, and IFN{gamma} were observed to be increased further in ventricular homogenates of 26-week-old MRL-lpr/lpr mice compared with 6-week-old autoimmune mice (Fig. 1AGo), and gene expression of IL-1ß and IL-6 was substantially elevated in the hearts of aged MRL-lpr/lpr mice compared with 26-week-old, immunologically normal CBA/J mice (Fig. 1BGo). Differences in cytokine gene expression in the ventricles of autoimmune and normal strains appeared to be selective since comparable expression of the genes encoding IL-3, TNF-{alpha}, and TGF-ß1 was observed (Fig. 1CGo). Analyses of the hearts of 6- and 26-week-old MRL-lpr/lpr mice revealed no leukocytes, fatty streaks, or plaques (data not shown). Thus, proinflammatory cytokine gene expression was increased in the hearts of autoimmune mice in the absence of either atherosclerotic lesions or mononuclear infiltrates.



View larger version (35K):
[in this window]
[in a new window]
  		Figure 1. Cytokine gene expression in the ventricles of autoimmune MRL-lpr/lpr and normal CBA/J mice. The ventricles were isolated from the hearts of young (6-week-old) and old (26-week-old) mice. cDNA was prepared, normalized, and amplified using cytokine-specific primers; polymerase chain reaction products were (B and C) separated on a 1% agarose gel then stained with ethidium bromide or (A) transferred to nylon membranes and subjected to Southern analysis.

 
To eliminate a possible contribution or spillover of cytokine mRNA from peripheral blood mononuclear cells to the above results, we isolated cardiac myocytes from 20-week-old MRL-lpr/lpr mice and age- and sex-matched immunologically normal CBA/J mice. mRNAs were extracted and reverse transcribed and cDNAs were amplified with primers as described above. The results (Fig. 2AGo) confirmed that constitutive gene expression of IL-1ß, IL-6, IL-10, and IFN{gamma} was increased in cardiac myocytes from aged MRL-lpr/lpr mice compared with immunologically normal CBA/J mice. Also consistent with our data in ventricular homogenates, no significant differences in the expression of genes encoding IL-3, TNF{alpha}, or TGFß1 were observed (Fig. 2BGo).



View larger version (46K):
[in this window]
[in a new window]
  		Figure 2. Cytokine gene expression in cardiomyocytes of autoimmune MRL-lpr/lpr and normal CBA/J mice. Cardiomyocytes were isolated from the hearts of 20-week-old mice. cDNA was prepared, normalized, and amplified using cytokine-specific primers; polymerase chain reaction products were separated on a 1% agarose gel then (B) stained with ethidium bromide or (A) transferred to nylon membranes and subjected to Southern analysis.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results show for the first time that ventricular myocytes from autoimmune MRL-lpr/lpr mice express high levels of genes that encode proinflammatory cytokines in the absence of histological evidence of either atherosclerosis or mononuclear cell infiltrates. Implicit in our findings is the suggestion that under conditions of chronic systemic inflammation, as occur in many connective tissue diseases, mediators derived from the myocardium may participate in the pathogenesis of heart disease.

It is notable that the gene encoding TNF{alpha} was not among those that were overexpressed in MRL-lpr/lpr cardiomyocytes. Tumor necrosis factor {alpha} drives inflammation in rheumatoid arthritis (RA), has been causally associated with vascular injury in chronic inflammatory states, and may induce the production of both IL-1ß and IL-6 (reviewed in Ref. 43). Although the gene encoding TNF{alpha} was equally expressed in autoimmune and normal cardiomyocytes, enhanced expression of IL-1ß and IL-6 was observed only in the setting of autoimmunity. One possible explanation for this finding is that TNF{alpha} mRNA is differentially regulated posttranscriptionally in autoimmune and normal hearts. However, to fully understand the discordance between the levels of TNF{alpha}, IL-1ß, and IL-6 mRNAs, as well as the significance of deregulated gene expression by autoimmune cardiomyocytes, concomitant cytokine protein measurements will need to be performed.

Our findings may be particularly relevant to diseases such as SLE and RA, which are typically accompanied by elevated plasma levels of proinflammatory cytokines when clinically active (44). These connective tissue diseases are associated with a significant incidence of cardiovascular disease, which occurs at a younger age than in the normal population (45). The observations described herein suggest that systemic inflammation, a consequence of poorly controlled disease activity in SLE and RA, may be accompanied by the production of proinflammatory cytokines by cardiac myocytes. Theoretically, these cytokines may act in a paracrine or autocrine fashion to promote the generation of pro-oxidant molecules, such as nitric oxide and superoxide, and ultimately generate damaging free radicals, such peroxynitrite and hydroxyl ion. In these patients, proinflammatory cytokines emanating from the heart, such as IL-1ß and IL-6, if produced in sufficient quantities may enter the periphery and transcriptionally upregulate hepatocytes to produce CRP. Viewed in this setting, CRP becomes a footprint of an ongoing pathogenic process mediated, in part, by the heart muscle itself.

Received for publication March 3, 2004. Accepted for publication June 18, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Boumpas DT, Austin HA 3rd, Fessler BJ, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: emerging concepts. Part 1: renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease. Ann Intern Med 122:940–950, 1995.
  2. Kotzin BL. Systemic lupus erythematosus. Cell 85:303–306, 1996.[Medline]
  3. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, Heyse SP, Hirsch R, Hochberg MC, Hunder GG, Liang MH, Pillemer SR, Steen VD, Wolfe F. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States [see comments]. Arthritis Rheum 41:778–799, 1998.[Medline]
  4. Mills JA. Systemic lupus erythematosus [see comments]. N Engl J Med 330:1871–1879, 1994.[Free Full Text]
  5. Chockalingam A, Prabhakar D, Gnanavelu G, Chockalingam V. Pancarditis as initial presentation of systemic lupus erythematosus. Int J Cardiol 87:111–114, 2003.[Medline]
  6. Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, D’Agostino RB, Kuller LH. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 145:408–415, 1997.[Abstract/Free Full Text]
  7. Bjornadal L, Yin L, Granath F, Klareskog L, Ekbom A. Cardiovascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish population based study 1964–95. J Rheumatol 31:713–719, 2004.[Medline]
  8. Sturfelt G, Eskilsson J, Nived O, Truedsson L, Valind S. Cardiovascular disease in systemic lupus erythematosus. A study of 75 patients form a defined population. Medicine (Baltimore) 71:216–223, 1992.[Medline]
  9. Moder KG, Miller TD, Tazelaar HD. Cardiac involvement in systemic lupus erythematosus. Mayo Clin Proc 74:275–284, 1999.[Medline]
  10. Bijl M, Brouwer J, Kallenberg GG. Cardiac abnormalities in SLE: pancarditis. Lupus 9:236–240, 2000.[Abstract/Free Full Text]
  11. Kao AH, Sabatine JM, Manzi S. Update on vascular disease in systemic lupus erythematosus. Curr Opin Rheumatol 15:519–527, 2003.[Medline]
  12. Moroni G, La Marchesina U, Banfi G, Nador F, Vigano E, Marconi M, Lotto A, Ponticelli C. Cardiologic abnormalities in patients with long-term lupus nephritis. Clin Nephrol 43:20–28, 1995.[Medline]
  13. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2399–2406, 2003.[Abstract/Free Full Text]
  14. Liuzzo G, Buffon A, Biasucci LM, Gallimore JR, Caligiuri G, Vitelli A, Altamura S, Ciliberto G, Rebuzzi AG, Crea F, Pepys MB, Maseri A. Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina. Circulation 98:2370–2376, 1998.[Abstract/Free Full Text]
  15. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina [see comments]. N Engl J Med 331:417–424, 1994.[Abstract/Free Full Text]
  16. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group [see comments]. Lancet 349:462–466, 1997.[Medline]
  17. Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group [see comments]. N Engl J Med 332:635–641, 1995.[Abstract/Free Full Text]
  18. Li SP, Goldman ND. Regulation of human C-reactive protein gene expression by two synergistic IL-6 responsive elements. Biochemistry 35:9060–9068, 1996.[Medline]
  19. Toniatti C, Arcone R, Majello B, Ganter U, Arpaia G, Ciliberto G. Regulation of the human C-reactive protein gene, a major marker of inflammation and cancer. Mol Biol Med 7:199–212, 1990.
  20. Fey GH, Fuller GM. Regulation of acute phase gene expression by inflammatory mediators. Mol Biol Med 4:323–338, 1987.[Medline]
  21. Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A 84:7251–7255, 1987.[Abstract/Free Full Text]
  22. Baumann H. Hepatic acute phase reaction in vivo and in vitro. In Vitro Cell Dev Biol 25:115–126, 1989.[Medline]
  23. Wijetunga M, Rockson S. Myocarditis in systemic lupus erythematosus. Am J Med 113:419–423, 2002.[Medline]
  24. Gerszten RE, Mach F, Sauty A, Rosenzweig A, Luster AD. Chemokines, leukocytes, and atherosclerosis. J Lab Clin Med 136:87–92, 2000.[Medline]
  25. Tellides G, Tereb DA, Kirkiles-Smith NC, Kim RW, Wilson JH, Schechner JS, Lorber MI, Pober JS. Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature 403:207–211, 2000.[Medline]
  26. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A 92:3893–3897, 1995.[Abstract/Free Full Text]
  27. Folcik VA, Aamir R, Cathcart MK. Cytokine modulation of LDL oxidation by activated human monocytes. Arterioscler Thromb Vasc Biol 17:1954–1961, 1997.[Abstract/Free Full Text]
  28. de Boer OJ, van der Wal AC, Verhagen CE, Becker AE. Cytokine secretion profiles of cloned T cells from human aortic atherosclerotic plaques. J Pathol 188:174–179, 1999.[Medline]
  29. Takano H, Ohtsuka M, Akazawa H, Toko H, Harada M, Hasegawa H, Nagai T, Komuro I. Pleiotropic effects of cytokines on acute myocardial infarction: G-CSF as a novel therapy for acute myocardial infarction. Curr Pharm Des 9:1121–1127, 2003.[Medline]
  30. Jougasaki M, Leskinen H, Larsen AM, Cataliotti A, Chen HH, Burnett JC Jr. Leukemia inhibitory factor is augmented in the heart in experimental heart failure. Eur J Heart Fail 5:137–145, 2003.[Medline]
  31. Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol 37:269–390, 1985.[Medline]
  32. al-Janadi M, al-Balla S, al-Dalaan A, Raziuddin S. Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases. J Clin Immunol 13:58–67, 1993.[Medline]
  33. Dean GS, Tyrrell-Price J, Crawley E, Isenberg DA. Cytokines and systemic lupus erythematosus. Ann Rheum Dis 59:243–251, 2000.[Free Full Text]
  34. Santoro TJ, Malek TR, Rosenberg YJ, Morse HC 3rd, Steinberg AD. Signals required for activation and growth of autoimmune T lymphocytes. J Mol Cell Immunol 1:347–356, 1984.[Medline]
  35. Theofilopoulos AN. The basis of autoimmunity: Part II. Genetic predisposition. Immunol Today 16:150–159, 1995.[Medline]
  36. Sheehan DC, Hrapchak BB. Theory and Practice of Histotechnology. St. Louis: Mosby, pp20–35, 1980.
  37. Santoro T, Maguire J, McBride OW, Avraham KB, Copeland NG, Jenkins NA, Kelly K. Chromosomal organization and transcriptional regulation of human GEM and localization of the human and mouse GEM loci encoding an inducible Raslike protein. Genomics 30:558–564, 1995.[Medline]
  38. Cai X, Foster CS, Liu JJ, Kupferman AE, Filipec M, Colvin RB, Lee SJ. Alternatively spliced fibronectin molecules in the wounded cornea: analysis by PCR. Invest Ophthalmol Vis Sci 34:3585–3592, 1993.[Abstract/Free Full Text]
  39. Maguire J, Santoro T, Jensen P, Siebenlist U, Yewdell J, Kelly K. Gem: an induced, immediate early protein belonging to the Ras family. Science 265:241–244, 1994.[Abstract/Free Full Text]
  40. Tomita M, Holman BJ, Santoro TJ. Aberrant cytokine gene expression in the hippocampus in murine systemic lupus erythematosus. Neurosci Lett 302:129–132, 2001.[Medline]
  41. Tomita M, Holman BJ, Williams LS, Pang KC, Santoro TJ. Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus. J Neurosci Res 64:26–33, 2001.[Medline]
  42. Hilal-Dandan R, Kanter JR, Brunton LL. Characterization of G-protein signaling in ventricular myocytes from the adult mouse heart: differences from the rat. J Mol Cell Cardiol 32:1211–1221, 2000.[Medline]
  43. Bacon PA, Stevens RJ, Carruthers DM, Young SP, Kitas GD. Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmun Rev 1:338–347, 2002.[Medline]
  44. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 423:356–361, 2003.[Medline]
  45. Schattner A, Liang MH. The cardiovascular burden of lupus: a complex challenge. Arch Intern Med 163:1507–1510, 2003.[Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tomita, M.
Right arrow Articles by Santoro, T. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tomita, M.
Right arrow Articles by Santoro, T. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS