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Thiazolidinedione (Pioglitazone) Blocks P. gingivalis- and F. nucleatum, but not E. coli, Lipopolysaccharide (LPS)-induced Interleukin-6 (IL-6) Production in Adipocytes
M. Yamaguchi1,
F. Nishimura1,*,
H. Naruishi1,
Y. Soga1,
S. Kokeguchi2 and
S. Takashiba1
1 Department of Patho-physiology/Periodontal Science, and
2 Oral Microbiology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8525, Japan;
Correspondence: * corresponding author, fusanori{at}md.okayama-u.ac.jp
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ABSTRACT
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An elevated level of C-reactive protein (CRP) predicts the future development of coronary heart disease. Periodontitis appears to up-regulate CRP. CRP is produced by hepatocytes in response to interleukin-6 (IL-6). A major source of IL-6 in obese subjects is adipocytes. We hypothesized that lipopolysaccharide (LPS) from periodontal pathogens stimulated adipocytes to produce IL-6, and that the production was suppressed by the drugs targeted against insulin resistance, thiazolidinedione (pioglitazone), since this agent potentially showed an anti-inflammatory effect. Mouse 3T3-L1 adipocytes were stimulated with E. coli, P. gingivalis, and F. nucleatum LPS. The IL-6 concentration in culture supernatants was measured. All LPS stimulated adipocytes to produce IL-6. Although pioglitazone changed adipocyte appearance from large to small, and completely suppressed P. gingivalis and F. nucleatum LPS-induced IL-6 production, E. coli LPS-induced IL-6 production was not efficiently blocked. Thus, pioglitazone completely blocked periodontal-bacteria-derived LPS-induced IL-6 production in adipocytes, a major inducer of CRP.
Key Words: diabetes • adipocyte • insulin resistance • thiazolidinedione • interleukin-6
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INTRODUCTION
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Diabetic subjects develop coronary heart disease more frequently as compared with non-diabetic subjects (Bierman, 1992). An elevated level of C-reactive protein (CRP), although often, for the most part, in a healthy reference range, has been reported to predict the future development of coronary heart disease (Ridker et al., 1997). Although it is still inconclusive as to whether elevation of CRP is simply a sensitive marker of inflammation, or whether increased circulating CRP directly exhibits pathological mechanisms promoting vascular disorders, there is growing evidence that CRP directly participates in the pathogenesis of vascular disorders via several distinct mechanisms (Rattazzi and Kushner, 2003). CRP is produced by hepatocytes in response to interleukin-6 (IL-6) (Gabay and Kushner, 1999). One of the major sources of IL-6 is believed to be adipose tissue in obese and/or obese-diabetic subjects (Coppack, 2001). Obesity is strongly associated with increased insulin resistance. In this connection, peroxisome proliferator-activated receptor (PPAR) activator, such as thiazolidinedione, has been demonstrated to improve insulin sensitivity and is currently being widely used for therapeutic purposes in obese-diabetic subjects (Willson et al., 2001). The hallmark of the pharmacological action of thiazolidinedione appears to be to increase the number of small, premature adipocytes without changing the adipose tissue mass (Okuno et al., 1998). In fact, thiazolidinedione has been reported to lower the expression of tumor necrosis factor- (TNF-)—an important adipocytokine responsible for insulin resistance—in adipocytes (Okuno et al., 1998). However, the effect of thiazolidinedione on IL-6 production in adipocytes has not yet been well-addressed.
Recent epidemiological studies have suggested that periodontal disease is associated with enhanced atherogenesis (Beck et al., 1998). CRP values are elevated in severe periodontitis patients (Slade et al., 2000; Noack et al., 2001; Nishimura et al., 2002), as measured by highly sensitive assays, and decrease with therapy (Iwamoto et al., 2003). In this study, therefore, we hypothesized that (1) bacterial lipopolysaccharide (LPS) derived from periodontal pathogens stimulated adipocytes to produce IL-6, and (2) thiazolidinedione would suppress LPS-induced IL-6 production in adipocytes.
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MATERIALS & METHODS
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Preparation of Bacterial LPS
Bacterial LPS from 3 distinct micro-organisms were used. Porphyromonas gingivalis FDC381 LPS and Fusobacterium nucleatum ATCC 25586 LPS were prepared by hot-phenol water extraction as described previously (Onoue et al., 2003), while E. coli LPS was purchased from Sigma (St. Louis, MO, USA).
Cells and Culture Conditions
Cultured mouse 3T3-L1 cells were differentiated to mature adipocytes as described previously (Bernlohr et al., 1984). Briefly, ATCC 3T3-L1 cells were cultured in growth medium containing Dulbecco’s modified Eagle’s medium (DMEM, Life Technologies, Inc., Gaithersburg, MD, USA) and 10% bovine calf serum (SIGMA), with a change of medium every 2 days. Two-day-post-confluent cells were switched to differentiation medium (DMEM, 10% fetal calf serum, 1 µM dexamethasone, 10 µg/mL insulin, and 0.5 mM 3-methyl-1-isobutylxanthin [Sigma]) for 2 days. Thereafter, the cells were cultured in post-differentiation medium (DMEM, 10% fetal calf serum, and 10 µg/mL insulin), and the medium was changed every 2 days. We confirmed differentiation and maturation of adipocytes by staining the cells with oil red O (Sigma). Following confirmation of full maturation, these cells were cultured with indicated concentration of thiazolidinedione. Pioglitazone (Actos), which was a generous gift from Takeda Pharmaceuticals (Osaka, Japan), was used as the thiazolidinedione. The changes in the appearance of adipocytes by thiazolidinedione were observed by microscopy. To quantify the changes in adipocyte appearance, we manually traced adipocyte size (diameter) on digital photographs at high power (400x). In a second experiment, the cells were challenged with each bacterial LPS at indicated concentrations. To see the effect of thiazolidinedione on LPS-induced IL-6 production, we co-incubated LPS-challenged adipocytes with pioglitazone. Twenty-four and 48 hrs after LPS stimulation, culture supernatants were collected. IL-6 concentrations in culture supernatants were measured with the use of a commercial sandwich ELISA kit (R&D Systems, Minneapolis, MN, USA). All experiments were performed in triplicate, and the results from these triplicate experiments were subjected to statistical analysis.
Statistical Analysis
Significance of the difference in IL-6 production in each culture condition was determined by Student’s t test.
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RESULTS
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Thiazolidinedione Changes Adipocyte Appearance
The effect of thiazolidinedione on changes in adipocyte appearance was examined first. After we confirmed the maturation of adipocytes by staining the cells with oil red O (Fig. 1A ), we co-cultured the cells with the indicated concentrations of pioglitazone. Pioglitazone changed adipocyte size from large to small in a dose-dependent manner (Fig. 1B). These changes were observed at 1 µM of pioglitazone. To quantify these changes, we compared the diameters of oil-red-stained cells (Fig. 1C). Both 1 and 10 µM of pioglitazone reduced adipocyte diameter by 40 to 50% (p < 0.01; Student’s t test).
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Figure 1. The effect of pioglitazone on the morphology of mouse 3T3-L1 adipocytes. Mouse 3T3-L1 adipocytes were differentiated into mature adipocytes as in MATERIALS & METHODS. We confirmed maturation by staining the cells with oil red O (A: right panel). When more than 95% of the cells were stained with oil red O, similarly prepared cells were co-incubated with indicated concentrations of pioglitazone. Twenty-four hrs later, the cells were stained with oil red O, and the morphology of the cells was observed by microscopy. Pioglitazone changed adipocyte appearance from large to small size (B). For comparison, the diameters of 10 randomly selected oil-red-positive cells per high-power field (400x) were measured and compared (C). The data were expressed as % diameter of the cells against the mean diameter (N = 10) of control (untreated) cells. The mean diameter of adipocytes significantly decreased by 1 µM and 10 µM of pioglitazone (100.0 ± 11.3% for pioglitazone-untreated cells, 61.7 ± 17.7% for 1 µM pioglitazone-treated cells, 54.3 ± 18.8% for 10 µM pioglitazone-treated cells, N = 10 for all groups). *p < 0.01, compared with the cells without pioglitazone.
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LPS Increased Il-6 Production in Adipocytes
Next, we examined the effects of bacterial LPS on IL-6 production in adipocytes (Figs. 2, 3, 4). All LPS at a concentration of 10 ng/mL or more significantly stimulated adipocytes to produce IL-6, as compared with control (medium alone) (Figs. 2, 3, 4; p < 0.01). E. coli LPS at a concentration of 1 ng/mL also significantly stimulated adipocytes to produce IL-6 (Fig. 2; p < 0.0001), while P. gingivalis LPS with 1 ng/mL did not show any effect on IL-6 production (Fig. 3). Thus, E. coli LPS showed the highest IL-6 productivity.
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Figure 2. The effects of E. coli LPS on IL-6 production, and of pioglitazone on E. coli LPS-induced IL-6 production in adipocytes. Mouse 3T3-L1 adipocytes were differentiated in 24-well tissue culture plates as described in MATERIALS & METHODS. After confirming the maturation of adipocity by staining the cells with oil red O, we stimulated the cells with indicated concentrations of E. coli LPS. In some cultures, the cells were co-incubated with 10 µM of pioglitazone. Twenty-four hrs later, the cell-culture supernatants were harvested, and the IL-6 concentration was measured by ELISA. All experiments were done in triplicate, and statistical differences were calculated by Student’s t test. In pioglitazone-treated cells, IL-6 production was compared with that of untreated cells when stimulated with the identical concentration of E. coli LPS. Mean IL-6 concentration ± standard deviation in each culture condition was calculated (1094.2 ± 68.6 pg/mL for LPS-unstimulated cells, 3189.7 ± 77.7 for 1 ng/mL of LPS-stimulated cells, 3271.5 ± 65.0 pg/mL for 10 ng/mL of LPS-stimulated cells, 3353.3 ± 53.2 pg/mL for 100 ng/mL of LPS-stimulated cells, 365.1 ± 5.0 pg/mL for LPS-unstimulated cells co-incubated with pioglitazone, 2087.4 ± 250.0 pg/mL for 1 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, 2181.5 ± 16.0 pg/mL for 10 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, and 2331.9 ± 11.8 pg/mL for 100 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, N = 3 for all groups). *p < 0.005 and **p < 0.0001, compared with the cells stimulated with the same concentration of LPS in the absence of pioglitazone.
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Figure 3. The effects of P. gingivalis LPS on IL-6 production, and of pioglitazone on P. gingivalis LPS-induced IL-6 production in adipocytes. Mouse 3T3-L1 adipocytes were differentiated in 24-well tissue culture plates as described in MATERIALS & METHODS. After confirming maturation of adipocity by staining the cells with oil red O, we stimulated the cells with indicated concentrations of P. gingivalis LPS. In some cultures, the cells were co-incubated with 10 µM of pioglitazone. Twenty-four hrs later, the cell-culture supernatants were harvested, and the IL-6 concentration was measured by ELISA. All experiments were done in triplicate, and statistical differences were calculated by Student’s t test. In pioglitazone-treated cells, the IL-6 production was compared with that of untreated cells when stimulated with the identical concentration of P. gingivalis LPS. Mean IL-6 concentration ± standard deviation in each culture condition was calculated (1094.2 ± 68.6 pg/mL for LPS-unstimulated cells, 1097.0 ± 13.2 pg/mL for 1 ng/mL of LPS-stimulated cells, 1796.9 ± 57.7 pg/mL for 10 ng/mL of LPS-stimulated cells, 1794.7 ± 8.2 pg/mL for 100 ng/mL of LPS-stimulated cells, 365.1 ± 5.0 pg/mL for LPS-unstimulated cells co-incubated with pioglitazone, 299.2 ± 1.8 pg/mL for 1 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, 267.9 ± 4.1 pg/mL for 10 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, and 372.4 ± 9.5 pg/mL for 100 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, N = 3 for all groups). **p < 0.0001, compared with the cells stimulated with the same concentration of LPS in the absence of pioglitazone.
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Figure 4. The effects of F. nucleatum LPS on IL-6 production, and of pioglitazone on F. nucleatum LPS-induced IL-6 production in adipocytes. Mouse 3T3-L1 adipocytes were differentiated in 24-well tissue culture plates as described in MATERIALS & METHODS. After confirming maturation of adipocity by staining the cells with oil red O, we stimulated the cells with indicated concentrations of F. nucleatum LPS. In some cultures, the cells were co-incubated with 10 µM of pioglitazone. Twenty-four hrs later, the cell-culture supernatants were harvested, and the IL-6 concentration was measured by ELISA. All experiments were done in triplicate, and the statistical differences were calculated by Student’s t test. In pioglitazone-treated cells, the IL-6 production was compared with that of untreated cells when stimulated with the identical concentration of F. nucleatum LPS. Mean IL-6 concentration ± standard deviation in each culture condition was calculated (1094.2 ± 68.6 pg/mL for LPS-unstimulated cells, 1308.3 ± 33.6 pg/mL for 1 ng/mL of LPS-stimulated cells, 1283.8 ± 6.4 pg/mL for 10 ng/mL of LPS-stimulated cells, 1552.9 ± 42.7 pg/mL for 100 ng/mL of LPS-stimulated cells, 365.1 ± 5.0 pg/mL for LPS-unstimulated cells co-incubated with pioglitazone, 223.7 ± 11.8 pg/mL for 1 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, 236.0 ± 5.9 pg/mL for 10 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, and 383.8 ± 5.5 pg/mL for 100 ng/mL of LPS-stimulated cells co-incubated with pioglitazone, N = 3 for all groups). **p < 0.0001, compared with the cells stimulated with the same concentration of LPS in the absence of pioglitazone.
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Thiazolidinedione Completely Blocks P. gingivalis and F. nucleatum LPS-induced IL-6 Production in Adipocytes
We then examined the effect of thiazolidinedione on LPS-stimulated IL-6 production in adipocytes (Figs. 2 , 3, 4). Although pioglitazone significantly suppressed E. coli LPS-induced IL-6 production in adipocytes, the suppression was not complete. About 30% reduction was observed (p < 0.005), as compared with the condition with LPS stimulation alone (Fig. 2). In contrast, pioglitazone completely blocked P. gingivalis and F. nucleatum LPS-induced IL-6 production (Figs. 3, 4; p < 0.0001 at all LPS concentrations). Pioglitazone also suppressed basal IL-6 production (without LPS stimulation) at the p < 0.0001 level of significance.
In a separate experiment, we measured IL-6 production from the cells incubated with LPS for 48 hrs. The results were very similar to those obtained from 24-hour incubation, suggesting that IL-6 production occurred during the first 24 hrs (data not shown).
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DISCUSSION
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Mild elevation of CRP has been suggested to be a sensitive marker for predicting the future development of coronary heart disease (Ridker et al., 1997). This may detect early but already ongoing vascular inflammation. However, recent studies have demonstrated that CRP is not merely a sensitive marker but also actively participates in the progression of atherosclerosis by binding to LDL-cholesterol, which makes the LDL-cholesterol-CRP complex more easily taken up by macrophages, leading to the formation of foam cells. CRP also stimulates endothelial cells to express adhesion molecules as intercellular adhesion molecule-1, which makes vascular endothelium easily bind to inflammatory cells. CRP promotes smooth-muscle-cell proliferation and chemotaxis, both of which promote atherosclerotic changes (for review, see Rattazzi et al., 2003).
CRP is produced by hepatocytes in response to IL-6. The major source of IL-6 in obese diabetic subjects is adipocytes, since obese subjects are characterized by increased circulating IL-6, and successful weight loss results in decreased serum IL-6 concentration (Ziccardi et al., 2002). Several reports have demonstrated that periodontal infection also up-regulates CRP (Slade et al., 2000; Noack et al., 2001; Nishimura et al., 2002), and periodontal treatment decreases CRP (Iwamoto et al., 2003). These observations suggest that severe periodontal infection results in increased IL-6 synthesis in the liver, to produce CRP. Although a previous study had reported that periodontal disease was associated with elevated circulating IL-6 concentration, the elevation was very weak and might be insufficient to stimulate hepatocytes to produce CRP (Loos et al., 2000). Therefore, we hypothesized that the source of IL-6 in severe periodontitis patients should be either Kupfer cells in the liver and/or adipocytes, in the case of fatty liver. In fact, most circulating antigens are cleared in the liver by means of so-called ‘hepatic clearance’. Thus, we hypothesized that infected antigens are concentrated in the liver, and that the concentration was higher than in other organs. It has been suggested that the circulating LPS concentration in some periodontitis subjects is more than 1 ng/mL (Vilkuna-Rautiainen et al., 2003, unpublished observations). Therefore, at least in the liver, the LPS concentration should be higher than this concentration.
Although a previous study has suggested that adipocytes express both toll-like receptors (TLR)-2 and -4 (Lin et al., 2000), it is still unclear whether the adipocytes produce IL-6 in response to bacterial LPS via such receptors. Therefore, in this study, we chose E. coli and F. nucleatum LPS, both of which bind TLR-4, and P. gingivalis LPS, whose action appears to be mediated through TLR-2 (Bainbridge and Darveau, 2001). The results indicated that activation of both TLR-2 and -4 in adipocytes induced IL-6 production, with higher productivity via the TLR-4-mediated pathway.
Although precise pharmacological actions of PPAR activators have not yet been fully elucidated, some previous studies have suggested that they suppress NF- B activity by competing with the binding proteins essential for nuclear translocation (Ruan et al., 2003) or by inhibiting the transcriptional regulatory functions of NF-B (Chinetti et al., 1998). Therefore, PPAR activator effectively suppresses tumor necrosis factor- (TNF-) production in adipocytes, an important adipocytokine responsible for insulin resistance (Uysal et al., 1997). Thus, the improvement of insulin sensitivity by thiazolidinedione is at least partially explained by decreased TNF- synthesis in adipose tissues. Moreover, thiazolidinedione has been suggested to exhibit anti-inflammatory properties (Ricote et al., 1998), and to be effective not only in patients with type 2 diabetes but also in immune-related diseases such as rheumatoid arthritis (Oates et al., 2002). Since monocytes from diabetic subjects were reported to over-produce TNF-, and since this over-production has been suggested to be one of the mechanisms responsible for enhanced periodontal tissue breakdown in such subjects (Salvi et al., 1997), thiazolidinedione would have an additive effect in preventing the progression of periodontal disease itself in patients with diabetes. Such a clinical study would be interesting, since this reagent has already been marketed clinically.
In conclusion, pioglitazone completely blocked periodontal-bacteria-derived LPS-induced IL-6 production in adipocytes, a major inducer of CRP.
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ACKNOWLEDGMENTS
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This work was supported by Grants-in-Aid from the Japan Society for the Promotion of Science (Nos. 15209071, 15791238, 15390566, and 16659499).
Received for publication January 15, 2004.
Revision received November 11, 2004.
Accepted for publication December 3, 2004.
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REFERENCES
|
|---|
- Bainbridge BW, Darveau RP (2001). Porphyromonas gingivalis lipopolysaccharide: an unusual pattern recognition receptor ligand for the innate host defense system. Acta Odontol Scand 59:131–138.[CrossRef][Medline]
[Order article via Infotrieve]
- Beck JD, Offenbacher S, Williams R, Gibbs P, Garcia R (1998). Periodontitis: a risk factor for coronary heart disease? Ann Periodontol 3:127–141.[Medline]
[Order article via Infotrieve]
- Bernlohr DA, Angus CW, Lane MD, Bolanowski MA, Kelly TJ Jr (1984). Expression of specific mRNAs during adipose differentiation: identification of an mRNA encoding a homologue of myelin P2 protein. Proc Natl Acad Sci USA 81:5468–5472.[Abstract/Free Full Text]
- Bierman EL (1992). George Lyman Duff Memorial Lecture. Atherogenesis in diabetes. Arterioscler Thromb 12:647–656.[Free Full Text]
- Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, et al. (1998). Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 273:25573–25580.[Abstract/Free Full Text]
- Coppack SW (2001). Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356.[Medline]
[Order article via Infotrieve]
- Gabay C, Kushner I (1999). Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448–454.[Free Full Text]
- Iwamoto Y, Nishimura F, Soga Y, Takeuchi K, Kurihara M, Takashiba S, et al. (2003). Antimicrobial periodontal treatment decreases serum C-reactive protein, tumor necrosis factor-alpha, but not adiponectin levels in patients with chronic periodontitis. J Periodontol 74:1231–1236.[CrossRef][Medline]
[Order article via Infotrieve]
- Lin Y, Lee H, Berg AH, Lisanti MP, Shapiro L, Scherer PE (2000). The lipopolysaccharide-activated Toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes. J Biol Chem 275:24255–24263.[Abstract/Free Full Text]
- Loos BG, Craandijk J, Hoek FJ, Wertheim-van Dillen PM, van der Velden U (2000). Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol 71:1528–1534.[CrossRef][Medline]
[Order article via Infotrieve]
- Nishimura F, Taniguchi A, Iwamoto Y, Soga Y, Fukushima M, Nagasaka S, et al. (2002). Porphyromonas gingivalis infection is associated with elevated C-reactive protein in nonobese Japanese type 2 diabetic subjects. Diabetes Care 25:1888.[Free Full Text]
- Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ, De Nardin E (2001). Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol 72:1221–1227.[CrossRef][Medline]
[Order article via Infotrieve]
- Oates JC, Reilly CM, Crosby MB, Gilkeson GS (2002). Peroxisome proliferators-activated receptor gamma agonists: potential use for treating chronic inflammatory diseases. Arthritis Rheum 46:598–605.[CrossRef][Medline]
[Order article via Infotrieve]
- Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, et al. (1998). Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 101:1354–1361.[Medline]
[Order article via Infotrieve]
- Onoue S, Imai T, Kumada H, Umemoto T, Kaca W, Isshiki Y, et al. (2003). Serum antibodies of periodontitis patients compared to the lipopolysaccharides of Porphyromonas gingivalis and Fusobacterium nucleatum. Microbiol Immunol 47:51–55.[Medline]
[Order article via Infotrieve]
- Rattazzi M, Puato M, Faggin E, Bertipaglia B, Zambon A, Pauletto P (2003). C-reactive protein and interleukin-6 in vascular disease: culprits or passive bystanders? J Hypertens 21:1787–1803.[CrossRef][Medline]
[Order article via Infotrieve]
- Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998). The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391:79–82.[CrossRef][Medline]
[Order article via Infotrieve]
- Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1997). Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973–979. Erratum in N Engl J Med 337:356, 1997.[Abstract/Free Full Text]
- Ruan H, Pownall HJ, Lodish HF (2003). Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J Biol Chem 278:28181–28192.[Abstract/Free Full Text]
- Salvi GE, Collins JG, Yalda B, Arnold RR, Lang NP, Offenbacher S (1997). Monocytic TNF alpha secretion patterns in IDDM patients with periodontal diseases. J Clin Periodontol 24:8–16.[CrossRef][Medline]
[Order article via Infotrieve]
- Slade GD, Offenbacher S, Beck JD, Heiss G, Pankow JS (2000). Acute-phase inflammatory response to periodontal disease in the US population. J Dent Res 79:49–57.
- Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997). Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614.[CrossRef][Medline]
[Order article via Infotrieve]
- Willson TM, Lambert MH, Kliewer SA (2001). Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 70:341–367.[CrossRef][Medline]
[Order article via Infotrieve]
- Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, et al. (2002). Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105:804–809.[Abstract/Free Full Text]
Journal of Dental Research, Vol. 84, No. 3,
240-244 (2005)
DOI: 10.1177/154405910508400306
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ABSTRACT
INTRODUCTION