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J Dent Res 84(4):324-328, 2005
© 2005 International and American Associations for Dental Research

RESEARCH REPORTS
Biological

Inflammation is More Persistent in Type 1 Diabetic Mice

D.T. Graves*, G. Naguib, H. Lu, C. Leone, H. Hsue, and E. Krall

Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Suite W-202D, 700 Albany Street, Boston, MA 02118, USA;

* corresponding author, dgraves{at}bu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Whether diabetes enhances or diminishes the host response to bacteria has been controversial. To determine how diabetes alters the inflammatory response, we inoculated P. gingivalis into the scalps of mice rendered diabetic with multiple low-dose streptozotocin treatment. On day 1, a moderate to severe inflammatory infiltrate was noted in both the diabetic and normoglycemic mice. After 3 days, the inflammatory infiltrate was significantly higher in the diabetic compared with the control group (P < 0.05). The mRNA expression of chemokines macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 was strongly and similarly induced 3 hrs and 1 day post-inoculation. By day 3, the levels were reduced in normoglycemic mice but remained significantly higher in the diabetic group (P < 0.05). To determine whether persistent inflammation was specific for the streptozotocin-induced diabetic model, we directly compared the expression of TNF-{alpha} in streptozotocin-induced and db/db diabetic mice, which developed type 2 diabetes. Both exhibited prolonged TNF-{alpha} expression compared with controls. These results suggest that diabetes alters bacteria-host interactions by prolonging the inflammatory response.

KEY WORDS: cytokine • hyperglycemia • inflammation • leukocyte • MIP-2 • MCP-1 • TNF-{alpha} • PMN • periodontal


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Diabetes mellitus has a dramatic impact on health, and its complications cause a high degree of morbidity and mortality (Libman et al., 1993). Although type 1 and type 2 diabetes have different etiologies, they share common symptoms: glucose intolerance, hyperglycemia, and hyperlipidemia. In addition, both types of diabetes have similar complications, ranging from vascular abnormalities and nephropathy to diminished wound healing (Singleton et al., 2003). They also exhibit increased susceptibility to infection and greater tissue loss following infection, as noted by more severe periodontitis (Löe, 1993; Cutler et al., 1999).

In vitro studies have been carried out to examine the effect of diabetes on the response of leukocytes to inflammatory stimuli such as lipopolysaccharide (LPS). It has been well-documented that diabetes inhibits important aspects of leukocyte function, such as chemotaxis and phagocytosis (Geerlings and Hopelman, 1999). However, inconsistent results have been reported for the effect of diabetes on cytokine expression. Some indicate diminished inflammatory cytokine expression, while others report enhanced expression (Salvi et al., 1997; Geerlings and Hopelman, 1999; Zykova et al., 2000; Furudoi et al., 2003).

P. gingivalis is an important oral pathogen. P. gingivalis infection causes gingival inflammation, spontaneous gingival bleeding, loss of connective tissue, and bone resorption (Holt et al., 1988; Socransky et al., 1999). It is frequently isolated from individuals with adult periodontitis, diabetes-associated periodontitis, and periodontal breakdown around dental implants (Listgarten and Lai, 1999; Socransky et al., 1999). P. gingivalis and other oral pathogens inoculated into the scalps of mice induce many of the same cellular responses associated with tissue destruction that occurs in human periodontitis (Zubery et al., 1998; Graves et al., 2001; He et al., 2004; Liu et al., 2004). That bacterial cell-wall components induce the same events as live bacteria suggests that host-bacteria interactions, rather than the direct effects of bacteria, are critical in the resulting tissue loss (Zubery et al., 1998; Chiang et al., 1999).

Since diabetes increases the risk of periodontal disease, we carried out studies to determine how diabetes alters the response to P. gingivalis. These studies focused on the impact of diabetes on the formation of a P. gingivalis-induced inflammatory infiltrate and chemokine expression in a type 1 model of diabetes. The goal of the study was to determine whether diabetes accelerated, prolonged, or increased the level of chemokine expression in response to P. gingivalis, and to determine whether there was also an effect on the formation of an inflammatory infiltrate.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Inoculation of P. gingivalis
P. gingivalis strain 381 was plated on bovine heart infusion agar at 37°C for 5 days in an atmosphere of 10% CO2, 10% H2, and 80% N2. Bacteria were collected during logarithmic growth and suspended in 50 µL of sterile PBS. Normoglycemic and diabetic mice were inoculated with P. gingivalis (5 x 108 or 1 x 108 bacteria/injection) at the midpoint of the scalp while anesthetized with ketamine (80 mg/kg) and xylazine (10 mg/kg). For each data point, there were 6 mice (n = 6).

Mice
CD-1 mice (Charles River Laboratories, Wilmington, MA, USA) were rendered diabetic by treatment with streptozotocin (40 micrograms per 1 g body weight) in 10 mM citrate buffer by intraperitoneal injection daily for 5 days. Control mice were treated identically, except that 10 mM citrate buffer alone was injected. In selected experiments, C57BLKslepr/lepr leptin-receptor-deficient mice, a model of type 2 diabetes, and normoglycemic control littermates (C57BLKs+/lepr) were used. Mice were considered to be diabetic when blood glucose levels exceeded 250 mg/dL. Mice were diabetic for 14 days prior to inoculation of bacteria. At the time experiments were initiated, serum glucose levels ranged from 325–450 mg/dL. Normoglycemic mice had serum glucose levels that ranged from 100–150 mg/dL. All procedures were approved by the Boston University Medical Center Institutional Animal Care and Use Committee.

Histologic Analysis
Following the death of the mice, the calvariae with intact soft tissue were fixed for 48 hrs in cold 4% paraformaldehyde and decalcified by incubation in cold Immunocal (Decal Corporation, Congers, NY, USA) and prepared for cryostat sections as previously described (Graves et al., 2001). Five-micrometer-thick sections were stained with hematoxylin and eosin. The degree of inflammation was characterized at the center of the inflammatory infiltrate. The following scale was used to assess the number of PMNs: 1, no PMNs; 3, slight infiltrate; 5, moderate infiltrate; 7, severe infiltrate; and 9, severe infiltrate with cell necrosis. Sections were analyzed under blind conditions. Six to eight fields were examined per section. Two sections were analyzed per animal so that the mean value for each animal could be established. For statistical purposes, the unit of measurement was the value of each animal. There were 6 animals per group (n = 6). The results presented are from one examiner, with the data confirmed by a second examiner.

Cytokine Expression
The scalps of the mice were dissected from the calvariae and immediately frozen in liquid nitrogen. Total RNA was extracted with Trizol (Life Technologies, Rockville, MD, USA) from pulverized frozen tissue, following the manufacturer’s instructions. We verified the concentration and integrity of the extracted RNA by denaturing agarose gel electrophoresis. Gene expression was measured by the RNase protection assay. 32P-labeled riboprobes were incubated with 12 µg of total RNA and then subjected to RNase digestion by means of a kit from Pharmingen (BD Biosciences, Franklin Lakes, NJ, USA), following the manufacturer’s instructions. Following electrophoresis on a 6% polyacrylamide gel, radiolabeled bands were visualized in a PhosphoImager (BioRad Laboratories, Hercules, CA, USA). The density of the protected bands was measured with Image ProPlus software (Media Cybernetics, Silver Spring, MD, USA), which was then normalized by the value of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the same lane. The mean densitometric values and standard deviation from 3 separate RNase protection assays are shown. The data are presented as the percent maximum divided by 100.

Statistical Analysis
Differences in mean inflammatory score and densitometric values between the experimental groups were evaluated with analysis of variance. The models included disease status and time of death as main effects and an interaction term for these effects. If the disease effect or interaction term was significant at p < 0.05, comparisons between diabetic and control groups at specific time points were performed with Student’s t tests. Data are presented as mean ± SEM. Values of p < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The inflammatory infiltrate that was produced by injection of P. gingivalis was assessed at the center of inflammation, where the recruitment of inflammatory cells was most intense. Inoculation of P. gingivalis (5 x 108) induced formation, one day later, of an inflammatory infiltrate consisting largely of PMNs. This was characterized by moderate to severe inflammation, with some cellular necrosis at the center of the infiltrate (Fig. 1Go). This inflammation subsided considerably by day 3. When inflammation was measured at the periphery, a similar pattern was obtained (data not shown).



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  		Figure 1. P. gingivalis stimulates formation of a more persistent inflammatory infiltrate in diabetic mice. Diabetes was induced by multiple low-dose streptozotocin treatment, while control mice were treated with citrate buffer alone. (A) P. gingivalis (5 x 108) or (B) P. gingivalis (1 x 108) was inoculated s.c. into the scalp. The degree of PMN infiltration was measured in H&E-stained sections at the center of the infiltrate. A scale was used ranging from no inflammation to severe inflammation with necrosis (0–9). Results are shown as mean ± SEM of 6 mice per group. *A significant difference (P < 0.05) between the control and diabetic groups.

 
To determine whether a similar result would be obtained at a different level of stimulation, we repeated the experiments with a lower bacterial inoculum (Fig. 1BGo). The inflammatory infiltrate that formed at the center was less severe compared with that formed when the higher dose of P. gingivalis was used (Fig. 1AGo). On day 1, there was a moderate inflammatory infiltrate formed at the center in both the diabetic and control groups. On day 3, there was a significant reduction in PMNs in the control group, with much less of a reduction in the diabetic group. The difference between controls and diabetics was significant only on day 3 (P < 0.05).

The inflammatory response was monitored at the molecular level by the expression of the cytokines MIP-2, MCP-1, and TNF-{alpha}. The expression of MIP-2 was strongly induced by P. gingivalis (5 x 108), reached high levels within 3 hrs, and remained high at 24 hrs (Fig. 2AGo). For both 3- and 24-hour time points, there was no difference between normoglycemic and diabetic mice (Fig. 2AGo) (P < 0.05). On day 3, however, the expression of MIP-2 decreased considerably in the control group, while it remained significantly higher in the diabetic group (P < 0.05). When a lower inoculum, 1 x 108 P. gingivalis, was tested, there was also no difference between the diabetic and control mice at the early time points, while there was a signficant difference at day 3 (Fig. 2BGo) (P < 0.05).



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  		Figure 2. Diabetes causes prolonged expression of MIP-2 in response to P. gingivalis. Diabetes was induced and P. gingivalis was inoculated into the scalp as described in Fig. 1Go. RNA was extracted from the soft tissue and analyzed by RPA. The density of each band was quantified and normalized according to the level of GAPDH expression in the same lane. Each value represents the mean of 3 different RPAs ± standard deviation. (A) P. gingivalis (5 x 108); (B) P. gingivalis (1 x 108). *A significant difference (P < 0.05) between the control and diabetic groups.

 
Inoculation of P. gingivalis stimulated MCP-1 expression (Fig. 3Go). Like MIP-2, MCP-1 mRNA levels were strongly induced within 3 hrs and were similar for the diabetic and control groups. For the high-dose inoculum, the level of MCP-1 remained high for control and diabetic groups on day 1 (Fig. 3AGo). On day 3, however, MCP-1 expression had subsided considerably in the normal mice, while it was still high in the diabetics. The difference between controls and diabetics on day 3 was significant (p < 0.05). For the lower-dose inoculum, MCP-1 levels at 24 hrs were reduced approximately 38% compared with those at 3 hrs, but there was no difference between control and diabetic mice (Fig. 3BGo). On day 3, the level of MCP-1 mRNA was lower in the control group compared with the diabetic group (P < 0.05).



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  		Figure 3. Diabetes causes prolonged expression of MCP-1 in response to P. gingivalis. Diabetes was induced and P. gingivalis was inoculated into the scalp as described in Fig. 1Go. RNA was extracted from the soft tissue and analyzed by RPA. The density of each band was quantified and normalized according to the level of GAPDH expression in the same lane. Each value represents the mean of 3 different RPAs ± standard deviation. (A) P. gingivalis (5 x 108); (B) P. gingivalis (1 x 108). *A significant difference (P < 0.05) between the control and diabetic groups.

 
It is possible that the results described above were specifically related to the streptozotocin model of diabetes, rather than to diabetes per se. To control for this possibility, we examined a second model of diabetes, the db/db mouse, that spontaneously develops type 2 diabetes (Leiter et al., 1981). TNF-{alpha} mRNA levels were assessed following P. gingivalis inoculation (Table). This cytokine was selected since it has been shown to be over-expressed in both type 1 and type 2 diabetic models (Hotamisligil and Spiegelman, 1994; Salvi et al., 1997). TNF-{alpha} mRNA levels were similarly induced by P. gingivalis in all mice on day 1. On day 3, the levels had gone down considerably in the control group (normoglycemic) mice for both models. In contrast, there was no reduction in TNF-{alpha} expression in the type 1 and type 2 diabetic mice.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The innate immune response has been shown to play an important role in periodontal disease (Williams et al., 1985; Graves, 1999). We examined several important parameters of the innate immune response to P. gingivalis, using a scalp model that is well-suited to examine host-bacteria interactions in vivo. The influence of diabetes was assessed in mice rendered diabetic by multiple low-dose treatment with streptozotocin. Unlike high-dose streptozotocin, the multiple low-dose model mimics several of the etiologic events that occur in the development of human type 1 diabetes (Like and Rossini, 1976). Most importantly, direct toxicity is low, and diabetes results from alterations in cells of the pancreas that cause them to be recognized as antigenic. Thus, multiple low-dose streptozotocin treatment induces an autoimmune insulitis that leads to insulin insufficiency and diabetes (Herold et al., 1996). The validity of the model is supported by findings that virtually identical results of prolonged TNF-{alpha} expression were noted in both the streptozotocin and the type 2 db/db diabetic models. This supports the concept that the impact of diabetes on the inflammatory response to infection is not dependent upon the type of diabetes, but rather is the consequence of hyperglycemia.

The inoculation of P. gingivalis in the type 1 diabetic model stimulated the formation of an inflammatory infiltrate that was proportional to the dose, particularly at the center of the infiltrate. For the 2 inocula, 5 x 108 and 1 x 108, the infiltrate formed was similar in the diabetic and control groups. However, diabetes caused a more persistent inflammatory infiltrate for both doses, as noted by the results on day 3. It is possible that the more prolonged inflammation in the diabetic group is due to differences in bacterial killing (Sima et al., 1988). However, this alone is unlikely to explain the results, since bacteria killed by paraformaldehyde fixation also stimulated prolonged inflammation in the diabetic group (data not shown).

The formation of an inflammatory infiltrate is controlled by the expression of inflammatory mediators, particularly chemokines. We noted rapid induction of chemokines in the diabetic and control groups at 3 and 24 hrs. This is in contrast to a report that diabetes impairs the early expression of chemokines, which in turn is associated with a delay in PMN infiltration (Amano et al., 2000). Our finding—that early expression of MIP-2, which is functionally equivalent to human IL-8, was similar in normal and diabetic mice—is consistent with histologic results demonstrating equivalent formation of an inflammatory infiltrate on day 1. Thus, the difference in our results compared with those of Amano and colleagues may reflect the site of inoculation and specific stimulus, i.e., inoculation of the lungs with LPS vs. subcutaneous injection of bacteria.

The issue of cytokine expression as a result of an infection in diabetes has been the subject of considerable controversy. There are reports indicating either depressed or enhanced cytokine expression as a result of the diabetic condition. In contrast, studies reported here indicate that there is a more prolonged inflammatory response. Prolonged expression of the chemokines MCP-1 and MIP-2, as well as the cytokines TNF-{alpha} and IL-6, in diabetic compared with normal animals has been shown to occur during wound healing (Wetzler et al., 2000; Goova et al., 2001). More persistent high levels of TNF-{alpha} have also been observed with an experimental buccal Streptococcal infection (Furudoi et al., 2003). We observed prolonged expression of MCP-1, MIP-2, and TNF-{alpha} in diabetic mice as a result of an experimental P. gingivalis infection, which provides a mechanism to explain the more persistent inflammatory infiltrate. Thus, by interfering with the down-regulation of inflammatory mediators, diabetes would cause a more persistent stimulus for the recruitment of leukocytes (Naguib et al., 2004). The more persistent inflammation could have multiple effects, including a tendency toward greater matrix degradation or a reduced capacity to repair injured tissue following bacteria-induced injury (Sodek and Overall, 1992; He et al., 2004; Liu et al., 2004).


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  		Table. TNF-{alpha} Levels in Two Different Models of Murine Diabetes
 

   ACKNOWLEDGMENTS
 
We thank Alicia Ruff for help in preparing this manuscript. This work was supported by grants from the National Institute of Dental and Craniofacial Research, DE11254 and DE13191.

Received March 23, 2004; Last revision January 4, 2005; Accepted January 12, 2005


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 DISCUSSION
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Furudoi S, Yoshii T, Komori T (2003). Balance of tumor necrosis factor alpha and interleukin-10 in a buccal infection in a streptozotocin-induced diabetic rat model. Cytokine 24:143–149.[ISI][Medline]

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