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Division of Endocrinology, Diabetes and Metabolism, State University of New York, and Kaleida Health, Buffalo, New York 14209
Address all correspondence and requests for reprints to: Paresh Dandona, M.D., Ph.D., Diabetes-Endocrinology Center of Western New York, 3 Gates Circle, Buffalo, New York 14209. E-mail: pdandona{at}kaleidahealth.org.
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Abstract |
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(PPAR) and a partial agonist of PPAR
in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPAR agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor 
B (NFB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured.
Blood glucose concentration changed significantly at 6 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF- and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFB-binding activity and plasma MCP-1, CRP, SAA, and TNF- did not change in the obese and obese diabetic control groups.
We conclude that rosiglitazone, a selective PPAR agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.
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Introduction |
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agonist with a partial PPAR agonist activity (1, 2). Troglitazone has an -tocopheroyl moiety in the molecule that may potentially contribute to its antioxidant and antiinflammatory activity. Troglitazone has now been withdrawn because of hepatotoxicity. Rosiglitazone, a selective and potent PPAR agonist, without a significant PPAR activity (3), is currently in therapeutic use, and we have, therefore, investigated its potential antiinflammatory effect. Rosiglitazone does not have an -tocopheroyl moiety in its molecular structure. Rosiglitazone has also been shown to possess an antiinflammatory effect in vitro (4, 5) and in animal models, including that of dextran sodium sulfate-induced colitis in the rat (6). An antiinflammatory and antioxidant effect of rosiglitazone would be of potential benefit in conditions such as atherosclerosis, which is characterized by a chronic inflammation of the arterial wall (7). Indeed, troglitazone (8) and pioglitazone (9) have been shown to reduce carotid arterial intimal-medial thickness; this phenomenon could be related causally to an antiinflammatory effect of thiazolidinediones. Because atherosclerosis is a major clinical complication associated with diabetes causing heart attacks and strokes, the presence of additional antiinflammatory properties in antidiabetic drugs will enhance the potential benefits of such drugs to reduce macrovascular disease.
The specific steps involved in inflammation at the molecular level are thought to be the activation of proinflammatory transcription factor nuclear factor B (NFB), usually a heterodimer of p65 (Rel A) and p50. Normally, NFB is located in the cytosol, where it is bound to inhibitor B (IB). In the nonphosphorylated state, IB binds to NFB and prevents its activation. This activation is achieved through the phosphorylation of the protein IB. Inflammatory signals, including endotoxin and proinflammatory cytokines, cause phosphorylation of IB, thus liberating and activating NFB. This allows NFB to translocate to the nucleus and to bind to and activate transcription of genes that are involved in the inflammatory response such as proinflammatory cytokines: TNF-, IL-6, IL-1ß, monocyte chemoattractant protein-1 (MCP-1), adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), and enzymes generating reactive oxygen species (ROS) (10, 11, 12, 13, 14, 15).
We have previously demonstrated antiinflammatory effects of several agents using the circulating mononuclear cells (MNCs) using indices described above. Thus, hydrocortisone (16, 17, 18), troglitazone (1, 2, 19), and insulin (20) have been shown to induce the suppression of intranuclear NFB and an increase in cellular IB in MNCs; a fall in ROS generation by MNCs, with a concomitant fall in the p47phox subunit, the key protein in NADPH oxidase (21, 22); and a fall in plasma concentration of TNF-, soluble ICAM-1 (sICAM-1), MCP-1, plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein (CRP). Our current study with rosiglitazone thus involves NFB and IB at the MNC level and CRP, sICAM-1, TNF-, and MCP-1 concentrations in plasma to address the hypothesis that rosiglitazone exerts an antiinflammatory effect in the two insulin-resistant states of obesity and type 2 diabetes.
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Subjects and Methods |
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Eleven obese nondiabetic subjects [seven females and four males; age, 42.1 ± 3.3 yr; body mass index (BMI), 37.9 ± 1.3 kg/m2] and 11 obese diabetic subjects (seven females and four males; age, 53.9 ± 2.5 yr; BMI, 38.5 ± 1.4 kg/m2) were included in the study (Table 1
). All subjects were given 4 mg daily of rosiglitazone for 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk. Eight obese subjects (six females and two males; age, 40.6 ± 1.4 yr; BMI, 36.1 ± 1.9 kg/m2) and five obese diabetic subjects (two females and three males; age, 55 ± 5.6 yr; BMI, 42 ± 5.6 kg/m2) were also included in the study as control groups. The recruitment of the control subjects was performed after that of the subjects given the active drug. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. The subjects were advised to continue their usual eating and exercise habits and other concomitant medications. The subjects’ body weight did not change during the period of the study. All subjects gave their written, informed consent, and the study protocol was approved by the Institutional Review Board.
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Blood samples were collected in Na-EDTA as an anticoagulant. The anticoagulated blood sample (3.5 ml) was carefully layered over 3.5 ml of the polymorphonuclear isolation medium (Robbins Scientific Corp., Sunnyvale, CA). Samples were centrifuged at 450 x g, in a swing-out rotor for 30 min at 22 C. At the end of the centrifugation, two bands separated out at the top of the red blood cell pellet. The top band consisted of MNC, whereas the bottom consisted of PMN isolation medium. The MNC band was harvested with a Pasteur pipette, repeatedly washed with Hanks’ balanced salt solution, and reconstituted to a concentration of 4 x 105 cells/ml in Hanks’ balanced salt solution. This method provides yields greater than 95% pure MNC suspension.
NFB EMSA
NFB gel retardation assay was performed as described previously (2, 17). DNA-binding protein extracts were prepared from MNCs by the method described by Andrews and Faller (23). Total protein concentrations were determined using bicinchoninic acid protein assay (Pierce, Rockland, IL). NFB gel retardation assay was performed using the NFB-binding protein detection kit (Life Technologies, Long Island, NY). Briefly, the double-stranded oligonucleotide containing a tandem repeat of the consensus sequence for the NFB binding site was radiolabeled with -P32 by T4 kinase. Then, 5 µg of the nuclear extract were mixed with the incubation buffer, and the mixture was preincubated at 4 C for 15 min. Labeled oligonucleotide (60,000 cpm) was added, and the mixture was incubated at room temperature for 20 min. Samples were then applied to wells of 6% nondenaturing polyacrylamide gel. The gel was dried under vacuum and exposed to x-ray film. Densitometry was performed using molecular analyst software (Bio-Rad, Hercules, CA).
p65 (Rel A) and IB Western blotting
Western blotting was performed as described previously (20, 24). Briefly, total protein concentrations were determined using bicinchoninic acid protein assay (Pierce). Twenty micrograms of total homogenates were used for SDS-PAGE. Western blotting was performed using polyclonal antibodies against NFB p65 (Rel A) and IB (Rockland, Gilbertsville, PA). Densitometric analysis of the Western blots was performed using molecular analyst software (Bio-Rad).
Plasma MCP-1, TNF-, sICAM-1, and CRP measurements
Plasma MCP-1, sICAM-1, and TNF- were assayed with ELISA kits from R&D Systems (Minneapolis, MN). The CRP ELISA kit was purchased from Diagnostic Systems Laboratories Inc. (Webster, TX).
Plasma insulin and glucose measurements
Insulin levels were determined using an ELISA kit from Diagnostic Systems Laboratories Inc. Glucose levels were measured in plasma by YSI 2300 STAT Plus glucose analyzer (YSI, Inc., Yellow Springs, OH).
Statistical analysis
Statistical analysis was performed using SigmaStat software (Jandel Scientific, San Rafael, CA). All data are expressed as mean ± SE. Analysis was performed with Kruskal-Wallis ANOVA on ranks. Dunnett’s method was used for all multiple comparison procedures. An unpaired t test was used to compare between the control group and rosiglitazone-treated group at each time point. Insulin and glucose concentrations were also analyzed by paired t test at time 0 and 6 wk.
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Results |
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Glucose concentrations did not change significantly after rosiglitazone intake in the nondiabetic obese subjects (Table 2). However, glucose concentration decreased significantly in the obese diabetic subjects at wk 6 (P < 0.05). Insulin concentration decreased significantly both in the nondiabetic obese and the obese diabetic subjects after rosiglitazone treatment (P < 0.05; Fig. 1). Glucose and insulin concentrations did not change significantly in the obese and obese diabetic control groups.
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B-binding activity, cellular p65 (Rel A), and IB protein contents
NFB-binding activity in MNC nuclear extracts was inhibited after rosiglitazone treatment in the obese and obese diabetic subjects. This inhibition was significant at wk 1 and continued to be inhibited up to wk 6 (P < 0.05; Fig. 2). NFB-binding activity continued to be inhibited at wk 12, 6 wk after the cessation of drug intake. There was no significant change in NFB-binding activity in the control groups (Fig. 2). There was a significant difference in NFB-binding activity between the rosiglitazone-treated and control groups at each time point at and after wk 2. In contrast, p65 (Rel A) protein levels in MNC did not change significantly after rosiglitazone treatment for 6 wk, nor did IB expression alter (data not shown).
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, and CRP concentrations
Basal plasma MCP-1 concentrations were 368 ± 37 pg/ml in the obese subjects and 411 ± 46 pg/ml in the obese diabetic subjects. MCP-1 concentrations decreased significantly in both groups after rosiglitazone intake for 6 wk (Fig. 3). This inhibition was significant after 1 wk of drug intake and continued to be inhibited after the withdrawal of the drug (P < 0.05). There was no change in plasma MCP-1 concentration in either the obese or the obese diabetic controls. There was a significant difference between the rosiglitazone-treated subjects and controls in terms of the changes in MCP-1 concentrations at each time point (Fig. 3) at and after wk 2. There was no significant change in plasma sICAM-1 concentration in any group (data not shown). The plasma TNF- level was inhibited significantly in the obese subjects from 3.1 ± 0.19 pg/ml (100%) to 93.5 ± 4.6% at d 3 and fell further at wk 1 to 86.4 ± 5.8% and continued to be inhibited thereafter (P < 0.05; Fig. 4). The plasma TNF- concentration did not change in the obese controls. The change in plasma TNF- concentration in the obese subjects after rosiglitazone was significantly greater than that in controls at each time point at and after wk 2 (Fig. 4). TNF- concentrations did not change in the obese diabetic subjects (Fig. 4). Plasma basal concentration of CRP in the obese subjects was 3.03 ± 0.39 µg/ml and was significantly lower than that in the obese diabetic subjects (6.06 ± 0.73 µg/ml; P < 0.05). CRP levels decreased significantly in both groups after rosiglitazone treatment at wk 1 and continued to be inhibited thereafter (P < 0.05; Fig. 5). CRP concentration returned to the basal level after the withdrawal of drug. Plasma CRP did not change in the obese and obese diabetic control groups. The change in plasma CRP concentrations after rosiglitazone treatment was significantly greater than that in controls at each time point at and after wk 2 (Fig. 5).
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Discussion |
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B in MNCs in both the nondiabetic obese and the obese diabetic subjects. These changes are consistent with a potent antiinflammatory effect of rosiglitazone at the cellular level. It is of interest that these effects were observed consistently in both groups despite the fact that the subjects were on a variety of drugs, especially in the diabetic group. We ensured that none of the subjects or controls altered their baseline drugs during the study. The suppression of NFB binding occurred much earlier than a fall in either insulin or glucose concentrations. Thus, the cellular antiinflammatory effect occurred directly before insulin sensitization or the glucose-lowering effect of rosiglitazone. We have previously demonstrated a similar action of troglitazone that induced an antiinflammatory effect at wk 1, whereas the glucose-lowering effect appeared after 4 wk. It would thus appear that as a class, thiazolidinediones probably exert an antiinflammatory effect as one of their primary actions. These data are also consistent with the fact that inflammation may contribute to insulin resistance.
It is of interest that although intranuclear NFB fell significantly after rosiglitazone, the level of p65 (Rel A) expression that has previously been shown to decline after troglitazone therapy (1, 2) did not alter, nor did the expression of IB change. This indicates that the decrease in intranuclear NFB was probably due to a direct interference in the binding of NFB to the promoters of proinflammatory genes. This would interfere with the transcription of proinflammatory genes. Whether higher doses of rosiglitazone suppress p65 (Rel A) expression and induce IB needs to be investigated. Glucocorticoids bound to the glucocorticoid receptor have previously been shown to inhibit NFB binding to the promoters of proinflammatory genes in addition to inducing IB and preventing the translocation of NFB into the nucleus (25, 26).
In addition to the cellular antiinflammatory effects, rosiglitazone caused a fall in plasma concentrations of CRP and MCP-1 in both the nondiabetic obese and the obese diabetic subjects. The plasma concentrations of CRP and MCP-1 fell significantly at wk 1, paralleling the fall in NFB. Whereas CRP represents an acute phase response to inflammation, MCP-1 is a specific proinflammatory chemokine, generated by endothelial cells and other inflammatory cells, inducing monocytes, for leukocytes to be chemoattracted to the inflammatory site (27, 28, 29). We have previously shown a fall in MCP-1 after troglitazone and insulin treatment (1, 2, 20). Insulin also reduces MCP-1 in human aortic endothelial cells in vitro (30). MCP-1 is a key proatherogenic mediator; it has been shown that the Apo E –/– mouse that develops atherosclerosis is prevented from doing so if there is a concomitant knockout of the MCP-1 gene (31). Troglitazone also caused a reduction in CRP in our previous studies. In the nondiabetic obese, there was a reduction in plasma TNF- concentrations as with troglitazone, within 1 wk of starting the drug.
Our recent demonstration that insulin also induces a reduction in intranuclear NFB in MNCs (20, 32) puts a new perspective on the antiinflammatory properties of thiazolidinediones. The fact that insulin and thiazolidinediones have similar potent antiinflammatory properties suggests that resistance to insulin action would cause a proinflammatory state. Thus, insulin-sensitizing thiazolidinediones probably reverse the insulin-resistant proinflammatory state to one toward normality; it is possible that the antiinflammatory and insulin-sensitizing effects are related. Indeed, we have recently demonstrated that the obese state is associated with nonsuppressible ROS generation and an increase in oxidative damage of lipids, proteins, and amino acids, all of which decrease with weight loss (33, 34). Recent data also show that there is an increase in TNF- and CRP, markers of inflammation in the obese subjects (35, 36). Plasma TNF- falls after weight loss (37). It would be of interest to examine whether thiazolidinedione-induced reduction of the inflammatory changes in the obese subjects is also observed in normal subjects.
In the above context, it is relevant that plasma CRP concentration has been shown to be a significant predictor of the development of type 2 diabetes in a nondiabetic population, independently of obesity and fasting insulin concentrations (38). Thus, inflammatory processes probably underlie the pathogenesis of type 2 diabetes. The ability of rosiglitazone to suppress inflammation in the nondiabetic obese subjects therefore suggests a potential role for rosiglitazone and possibly other thiazolidinediones in the prevention of type 2 diabetes. Indeed, Buchanan et al. (39) demonstrated that the treatment of women with a history of gestational diabetes with troglitazone leads to a marked reduction in the rate of development of type 2 diabetes in these women.
The absence of changes in TNF- in the obese diabetics after rosiglitazone needs comment. Differences in the effects of troglitazone on the obese and the obese diabetic subjects were also observed in our previous studies. Thus, TNF- concentrations did not fall after troglitazone in the obese diabetic subjects while they did so in the obese nondiabetic subjects. These effects may require higher doses of the drug or more prolonged periods of treatment. Glucose has been shown to exert proinflammatory effects that may result in an increase in the proinflammatory process, including an increase in TNF- mRNA in MNCs (40).
These data parallel the effects we have previously described with troglitazone (1, 2, 19). These antiinflammatory effects of rosiglitazone suggest that there may be a thiazolidinedione class effect and that the effects seen with troglitazone were not due to the -tocopheroyl moiety or a partial PPAR effect. They are also consistent with the recent observations by Haffner et al. (41) with rosiglitazone treatment for 26 wk, which caused a fall in plasma CRP concentrations in subjects with type 2 diabetes. Thus, thiazolidinediones, and possibly other PPAR agonists, have a potent antiinflammatory effect at the level of the MNC. This is important because MNCs, especially monocytes and T lymphocytes contained in MNC fraction, participate in the inflammatory changes on the endothelial surface and thereafter in the subendothelial intima as foam cells during the development of atherosclerosis (42, 43). Monocytes are known to form foam cells in the subendothelial intima that collectively form the fatty streak, the initial lesion of atherosclerosis (44, 45). In this context, it is relevant that we have observed a reduction in the expression of PPAR and a concomitant increase in PPAR in MNCs after therapy with troglitazone (46). Whether these changes are essential to or a concomitant part of the antiinflammatory effect of thiazolidinediones will require additional investigation. Furthermore, PPAR may regulate the expression of scavenger receptors and the formation of foam cells (47).
The major limitation of this study is its nonrandomized design and the absence of the use of placebo in control groups. However, it is clear that although the rosiglitazone-treated subjects, both obese and nonobese, had clear-cut early and persistent falls in NFB binding, plasma CRP, and MCP-1, concentrations, the controls did not demonstrate this fall. There was also a significant difference in the changes between the rosiglitazone-treated and control groups. It would thus appear that rosiglitazone does indeed exert an antiinflammatory effect at the cellular and molecular level both in the obese and the obese diabetics. Although this study is relatively short, the study by Haffner et al. (41) has previously demonstrated a reduction in plasma CRP concentrations after a longer period of rosiglitazone. The aim of our study was mainly to examine detailed cellular and molecular mechanisms involved in the antiinflammatory effects of rosiglitazone.
In conclusion, rosiglitazone, a PPAR-selective agonist, has potent antiinflammatory effects, and such effects probably characterize other PPAR agonists.
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Footnotes |
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Abbreviations: BMI, Body mass index; CRP, C-reactive protein; ICAM-1, intercellular adhesion molecule-1; IB, inhibitor B; MCP-1, monocyte chemoattractant protein-1; MNC, mononuclear cell; NFB, nuclear factor B; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; sICAM-1, soluble ICAM-1.
Received December 10, 2003.
Accepted March 1, 2004.
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