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Mechanism of Azithromycin Treatment on Gingival Overgrowth
J.-Y. Kim1,5,
S.-H. Park2,5,
K.-S. Cho2,3,
H.-J. Kim1,
C.-K. Lee1,4,
K.-K. Park1,3,4,
S.-H. Choi2,3 and
W.-Y. Chung1,3,4,*
1 Department of Oral Biology,
2 Department of Periodontology, Research Institute for Periodontal Regeneration,
3 Oral Science Research Institute, and
4 Brain Korea 21 Project, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752, South Korea
Correspondence: * corresponding author, wychung{at}yuhs.ac
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ABSTRACT
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Azithromycin is effective for the remission of cyclosporine A-induced gingival overgrowth (CIGO) in persons who have undergone renal transplant. To explain its mechanism in alleviating the clinical symptoms of these indivduals, we examined the effect of azithromycin on cell proliferation and collagen turnover modified by cyclosporin A in human gingival fibroblasts from healthy persons and from persons who had undergone renal transplant. Cyclosporin A-induced proliferation of renal transplant fibroblasts and normal fibroblasts was inhibited by azithromycin. Azithromycin elevated the reduced metalloproteinase (MMP)-1 and MMP-2 activities in cyclosporine A-treated renal transplant fibroblasts and normal fibroblasts. In cyclosporine A-treated renal transplant fibroblasts, azithromycin blocked the accumulation of total collagen in culture media and the increase in type I collagen mRNA level, but recovered the reduced MMP-2 mRNA level to the control. These results suggest that azithromycin may improve CIGO by blocking cyclosporine A-induced cell proliferation and collagen synthesis, and by activating MMP-2 in gingival fibroblasts of persons with cyclosporine A-induced gingival overgrowth.
Key Words: Cyclosporin A • gingival overgrowth • azithromycin • matrix metalloprotease-2
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INTRODUCTION
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Cyclosporin A is the most frequently used immunosuppressor for preventing organ transplant rejection (Wysocki et al., 1983). However, cyclosporine A therapy has various side-effects, including gingival overgrowth (Tyldesley and Rotter, 1984). Clinical and cellular studies have demonstrated that cyclosporine A affects the proliferation of gingival fibroblasts (Bartold, 1989) and the accumulation of connective tissue extracellular matrix (ECM) components. This accumulation results from the abnormal synthesis of ECM molecules, particularly collagen (Schincaglia et al., 1992; Gagliano et al., 2004), and/or a decrease in the degradation of ECM components. Cyclosporin A inhibits collagenase gene expression via activator protein-1 and c-Jun N-terminal kinase (Sugano et al., 1998), and reduces collagen degradation by lowering phagocytosis (Kataoka et al., 2000) and the activities of lysosomal enzymes cathepsin-B and -L in gingival fibroblasts (Yamaguchi et al., 2004).
Clinically, gingival overgrowth is treated with oral hygiene measures for plaque control, with partial gingivectomy in severe cases (Aimetti et al. 2005), and by switching to tacrolimus as an alternative to cyclosporine A (Bader et al., 1998; James et al., 2000). Furthermore, various case reports have described the efficacy and safety of azithromycin for the partial or complete remission of drug-induced gingival overgrowth (Gomez et al., 1997; Citterio et al., 2001; Tokgoz et al., 2004). The aim of this study was to explain the mechanism for how azithromycin alleviates the clinical symptoms without the reduction of cyclosporine A medication in persons with cyclosporine A-induced gingival overgrowth (CIGO). We investigated the effects of azithromycin on cyclosporine A-induced cell proliferation and collagen turnover.
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MATERIALS & METHODS
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Cell Culture
Human gingival fibroblasts were obtained from a primary explant culture of the gingival tissues from 10 healthy donors (normal fibroblasts; five males and five females, aged 31 to 50 yrs) without evidence of inflammation, hyperplasia, or history of taking drugs associated with gingival overgrowth, and from seven renal transplant recipients exhibiting CIGO (renal transplant fibroblasts; four males and three females, aged 37 to 55 yrs). Persons with cyclosporine A-induced gingival overgrowth had been taking cyclosporine A for at least 6 mos, and had not been taking any other drug that could affect their periodontal status for at least 3 mos. All participants were 30 yrs of age or older. The protocol was approved by the Institutional Review Board of Yonsei University College of Dentistry, Seoul, Korea. Informed consent was obtained from each participant. The gingival tissue was surgically excised under local anesthesia. After being washed and chopped, the pieces were incubated in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% antibiotic-antimycotic mixture at 37°C in a humidified atmosphere containing 5% CO2. The cells between passages 3 and 6 were used.
Cell Treatment with Cyclosporin A and Azithromycin
Due to their highly hydrophobic nature, 1 mg of cyclosporin A (Sigma, St. Louis, MO, USA) and 10 mg of azithromycin (Pfizer Inc., Groton, CT, USA) were dissolved in 1 mL of DMSO, respectively. The stock solutions were diluted with DMEM containing 2% FBS to the indicated concentrations of cyclosporin A or azithromycin. The control cells received the same concentration of DMSO used in each experiment.
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT) Assay
Renal transplant fibroblasts and normal fibroblasts (3 x 103 cells) were treated with 2% FBS-DMEM containing 10 ng/mL cyclosporin A and/or 50 µg/mL azithromycin for 3 and 5 days. A MTT solution (5 mg/mL) was added and incubated for 4 hrs at 37°C. The MTT solution was removed, and the remaining formazan products in the cells were dissolved with 100 µL of DMSO. The absorbance was measured at 570 nm.
5-Bromo-2'-deoxyuridine (BrdU) Incorporation Assay
We assessed cyclosporin A-induced proliferation of gingival fibroblasts by measuring BrdU incorporation into the newly synthesized DNA of proliferating cells. Renal transplant fibroblasts and normal fibroblasts (3 x 103 cells) were incubated in 2% FBS-DMEM containing 10 ng/ mL cyclosporin A and/or 50 µg/mL azithromycin for 5 days. The incorporation of BrdU into DNA was determined with a commercial BrdU Labeling and Detection Kit III (Roche, Mannheim, Germany) according to the manufacturer’s instructions.
Zymography
Renal transplant fibroblasts and normal fibroblasts (1 x 106 cells) were incubated in 2% FBS-DMEM with 10 ng/mL cyclosporin A and/or azithromycin at the indicated concentrations for 5 days. The medium was concentrated by means of a Centricon centrifugal filter device YM-10 (Millipore Corp., Bedford, MA, USA). The concentrated media were mixed with a non-reducing sample buffer [60 mM Tris-HCl (pH 6.8), 10% SDS, 12% sucrose, and 0.02% bromophenol blue]. A 30-µg quantity of total protein per sample was then run onto 10% sodium dodecyl sulphate polyacrylamide gel co-polymerized with either 1.6 mg/mL type I gelatin or 1.5 mg/ mL type I collagen from rat tails. The gels were washed twice in 2.5% Triton X-100 solution for 30 min at room temperature, and then incubated in an activation buffer containing 50 mM Tris-HCl (pH 7.5), 10 mM CaCl2, and 0.15 M NaCl for 16 hrs at 37°C. The activity of matrix metalloproteinase (MMP)-1 and MMP-2 was detected after the gels were stained with Coomassie brilliant blue R250 as clear bands in a blue background.
Collagen Assay
The amount of collagen in the culture media was assessed by means of a Sircol collagen assay kit (Biocolor, Galway, Ireland). Briefly, renal transplant fibroblasts (2 x 105 cells) were cultured in 2% FBS-DMEM with or without 10 ng/mL cyclosporin A and/or azithromycin at various concentrations for 5 days. The concentrated culture media (100 µL) were mixed with 100 µL Sircol dye and incubated for 30 min at room temperature. After centrifugation for 10 min at 12,000 g, the collagen-bound dye was resolved with 100 µL alkali reagent. The absorbance was measured at 540 nm.
Reverse-transcription Polymerase Chain-reaction (RT-PCR)
Detection of the mRNA encoding type I collagen, MMP-1, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 in renal transplant fibroblasts was performed by RT-PCR. Total cellular RNA was isolated from renal transplant fibroblasts with TRIZOL reagent (Life Technologies, Grand Island, NY, USA) and digested with RQ1 RNase-free DNase I (Promega, Madison, WI, USA). First-strand cDNA was synthesized with 1 µg total RNAs, 1 µM oligo-dT15 primer, and MMLV Reverse Transcriptase (Promega). Using the recombinant Taq DNA polymerase kit (Takara, Shiga, Japan), we performed PCR with 0.5 µfirst-strand cDNA and 10 pmole for each primer: type I collagen (347 bp), 5'-GGCGGCCAGGGCTCCGAC-3', 5 '-C C A C G G G G T C T G G T C C T T A A - 3 '; M M P - 1 ( 4 3 7 b p ), 5 '-A G G T C T C T G A G G G T C A A G C A - 3 ', 5 '-G A A C A T C A C T T C T C C C C G A A - 3 '; M M P - 2 ( 5 5 7 b p ), 5 '-G T C G C C C A T C A T C A A G T T C - 3 ', 5 '-C T C C C A A G G T C C A T A G C T C A - 3 '; T I M P -1 (438 bp), 5'-GTCAGTGGTGGACCTGACCT-3', 5 '-A G G G G T C T A C A T G G C A A C T G - 3 '; T I M P -2 ( 5 0 6 b p ), 5 '-G T C G C C C A T C A T C A A G T T C - 3 ', 5'-CTCCCAAGGTCCATAGCTCA-3'; and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (420 bp) as an endogenous control, 5'-TGTGTGACCCAGGACTACCA-3', 5'-ACTTGTTGAACATCCAGCCC-3'. PCR reaction consisted of initial denaturation at 94°C for 3 min, 30 cycles (type I collagen, 35 cycles) at 94°C for 50 sec (type I collagen, 94°C for 1 min), 52°C for 50 sec (type I collagen, 61°C for 90 sec), and 72°C for 1 min (type I collagen, 72°C for 2 min), and final extension at 72°C for 10 min. The amplified PCR products were separated by electrophoresis on a 1.5% agarose gel and visualized by staining with ethidium bromide. The net intensities of bands were quantified by image analysis software (TINA, version 2.0).
Statistical Analysis
Data are expressed as means ± SE of 3 independent experiments and analyzed via repeated measures of one-way ANOVA and Dunnett’s t test. P values of less than 0.05 were considered to be statistically significant.
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RESULTS
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Azithromycin Inhibits Cyclosporin A-induced Proliferation of Human Gingival Fibroblasts
To evaluate the effects of cyclosporin A and azithromycin on cell proliferation, we performed a MTT assay and a BrdU incorporation assay. Cell viability and DNA synthesis were significantly increased in renal transplant fibroblasts and normal fibroblasts treated with 10 ng/mL cyclosporin A for 5 days. Cyclosporin A-induced cell proliferation was much higher in renal transplant fibroblasts than in normal fibroblasts. The enhanced cell viability (Fig. 1A ) and DNA synthesis (Fig. 1B) by cyclosporin A treatment were remarkably inhibited by treatment with 50 µg/mL azithromycin. Azithromycin alone reduced cell viability, but had little effect on DNA synthesis.
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Figure 1. Effect of azithromycin on cyclosporin A-induced proliferation of renal transplant fibroblasts and normal fibroblasts. Renal transplant fibroblasts (CIGO-NGFs) and normal fibroblasts (N-HGFs) were obtained by a primary explant culture of the gingival tissues from renal transplant recipients exhibiting CIGO and from healthy donors, respectively. (A) Cell viability was estimated in CIGO-NGFs and N-HGFs cultured in 2% FBS-DMEM containing 10 ng cyclosporin A and/or 50 µg/mL azithromycin (AZI) for 3 and 5 days, by a MTT assay. (B) DNA synthesis was measured in CIGO-NGFs and N-HGFs treated with 10 ng cyclosporin A and/or 50 µ/mL AZI for 5 days, by a BrdU incorporation assay. Control received 0.01% DMSO alone. Data are expressed as mean ± SE of 3 individual experiments. #Significantly different from the control, p < 0.01, *Significantly different from cyclosporin A-treated cells, p < 0.01.
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Azithromycin Activates MMP-2 in Cyclosporin A-treated Renal Transplant Fibroblasts and Normal Fibroblasts
Zymographic analysis indicated that cyclosporin A treatment decreased the activities of MMP-1 and MMP-2 in renal transplant fibroblasts and normal fibroblasts. In contrast, azithromycin treatment restored the reduced activation of MMP-1 and MMP-2 in cyclosporin A-treated renal transplant fibroblasts and normal fibroblasts. However, cyclosporin A and azithromycin weakly affected MMP-1 compared with MMP-2 in renal transplant fibroblasts (Fig. 2A). MMP-2 in the conditioned media of renal transplant fibroblasts also showed its collagenolytic activity on the gel with type I collagen (Fig. 2B).
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Figure 2. Effect of azithromycin on MMP-1 and MMP-2 activity in renal transplant fibroblasts and normal fibroblasts. Renal transplant fibroblasts (CIGO-NGFs) and normal fibroblasts (N-HGFs) were incubated in 2% FBS-DMEM with 10 ng/mL cyclosporin A and/or azithromycin at the indicated concentrations for 5 days. The conditioned media were collected and concentrated. (A) MMP-1 activity was measured on a gel with type I collagen and MMP-2 activity on a gel with type I gelatin. (B) The activity of MMP-2 was detected on the gels with type I collagen or type I gelatin as a substrate. Purified MMP-1 or MMP-2 (S) was used to identify MMPs in conditioned media.
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Azithromycin Inhibits Cyclosporin A-induced Collagen Accumulation
The amount of total collagen in the culture media was assessed by a colorimetric assay with Sircol reagents. The level of collagen was elevated in the culture media of renal transplant fibroblasts stimulated with cyclosporin A for 5 days, and azithromycin suppressed cyclosporin A-induced collagen accumulation in a dose-dependent manner (Fig. 3). We have previously reported that cyclosporin A did not influence the amount of total collagen in the conditioned media of normal fibroblasts (Noh et al., 2003).
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Figure 3. Effect of azithromycin on cyclosporin A-induced collagen accumulation in the culture medium of renal transplant fibroblasts. Renal transplant fibroblasts (CIGO-NGFs) were incubated with various concentrations of azithromycin in the presence of cyclosporin A for 5 days. Collagen content in the concentrated conditioned medium was assessed by mean of a Sircol collagen assay kit. Data are means ± SE of 3 individual experiments. #Significantly different from the control, p < 0.05, *Significantly different from cyclosporin A-treated cells, p < 0.05.
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Azithromycin Inhibits the mRNA Level of Type I Collagen and Increases That of MMP-2
The mRNA levels of type I collagen, MMP-1, MMP-2, TIMP-1, and TIMP-2 were analyzed by RT-PCR (Fig. 4). The mRNA expression of type I collagen was up-regulated, and that of MMP-2 was down-regulated in the renal transplant fibroblasts exposed to cyclosporin A for 5 days. Azithromycin blocked these effects of cyclosporin A on the mRNA expression of type I collagen and MMP-2. However, cyclosporin A and azithromycin had no effect on the mRNA levels of MMP-1, TIMP-1, and TIMP-2.
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Figure 4. Effect of azithromycin on the mRNA expressions of type I collagen, MMP-1, MMP-2, TIMP-1, and TIMP-2 in renal transplant fibroblasts. The mRNA expression levels were evaluated by RT-PCR in renal transplant fibroblasts (CIGO-NGFs) cultured with or without 10 ng/mL cyclosporin A and azithromycin (AZI) at the indicated concentrations for 5 days. Each amplified cDNA was normalized to GAPDH gene expression. *Significantly different from cyclosporin A-treated cells, p < 0.01.
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DISCUSSION
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Clinically, CIGO is initially observed as a papillary enlargement, resulting in a lobulated appearance (Tyldesley and Rotter, 1984). Enlarged gingival tissue may allow the further accumulation of oral bacteria into the pockets and influence the clinical course of marginal periodontitis. Azithromycin improves clinical symptoms in persons with cyclosporine A-induced gingival overgrowth without changing the blood level of cyclosporin A and the renal function when azithromycin is administered orally (Kwun et al., 2003; Tokgoz et al., 2004). A recent study reported that azithromycin induced the remission of CIGO by compensating for the lowered phagocytic activity by cyclosporin A in rat gingival fibroblasts, resulting in an increase in collagen degradation (Paik et al., 2004). The present study is the first to explain the mechanism underlying azithromycin therapy on CIGO by examining the cellular and molecular effects of azithromycin on cell proliferation and collagen metabolism modified by cyclosporin A in human gingival fibroblasts.
Many studies investigating the effects of cyclosporin A on proliferation, collagen synthesis, and collagenolytic response of gingival fibroblasts have reported conflicting results due to their marked inter-individual differences to cyclosporin A (Schincaglia et al., 1992). The development and degree of gingival overgrowth are related to genetic predisposition, duration of cyclosporin A treatment, and oral hygiene status rather than to cyclosporin A dosage (Seymour and Jacobs, 1992) and the whole-blood cyclosporin A concentration (Pernu et al., 1992). In our preliminary experiments, we confirmed that the viability of renal transplant fibroblasts and normal fibroblasts was markedly raised at 10 ng/mL cyclosporin A when cultured with cyclosporin A ranging from 1 ng/mL to 100 ng/mL for 3 and 5 days. In addition, azithromycin alone reduced the viability of renal transplant fibroblasts and normal fibroblasts at more than 50 µg/mL (data not shown). In the present study, azithromycin significantly inhibited cyclosporin A-stimulated proliferation of renal transplant fibroblasts and normal fibroblasts by blocking DNA synthesis.
Disturbances in the collagen metabolism of gingival tissue rather than an increase in the number of fibroblasts have been considered to be a possible mechanism underlying the pathogenesis of CIGO (Nares et al., 1996; Seymour et al., 1996). The accumulation of collagen induced by cyclosporin A treatment is more closely associated with a lack of collagen breakdown than with an increase in collagen production (Kataoka et al., 2000). While the stimulating effect of cyclosporin A on type I collagen synthesis has been reported (Gagliano et al., 2004), some studies have demonstrated that collagen synthesis is not affected or inhibited by cyclosporin A in normal fibroblasts (Bartold, 1989). Immunohistological analysis in cases of GO demonstrated that type IV collagen was present in the cyclosporin A-treated gingiva in significantly higher amounts than in the healthy gingival, but the level of type III collagen was not significantly greater (Bonnaure-Mallet et al., 1995). MMPs are the primary enzymes responsible for the remodeling and degrading of the ECM. Although MMPs are broadly divided into interstitial collagenases, gelatinases, stromelysins, and membrane-type MMPs, substrate specificities on the ECM components tend to overlap. Most MMPs are closely regulated by TIMP-1 and TIMP-2 in periodontal lesions (Kubota et al., 1997; Kato et al., 2005). There is evidence suggesting that cyclosporin A significantly inhibits the mRNA level and/or activity of MMP-1 (Hyland et al., 2003; Gagliano et al., 2004), MMP-2 (Silva et al., 2001; Cotrim et al., 2002; Gagliano et al., 2004), and MMP-3 (Bolzani et al., 2000), thereby contributing to the extracellular matrix accumulation in CIGO. In contrast, other reports have shown that these MMPs were unaffected by cyclosporin A (Yamada et al., 2000; Tuter et al., 2002). Studies investigating the effect of cyclosporin A on TIMP-1 and TIMP-2 also showed inter-individual variations (Tuter et al., 2002; Gagliano et al., 2004; Yamaguchi et al., 2004). Analysis of our data indicated that cyclosporin A significantly reduced the activities of MMP-1 and MMP-2 in normal fibroblasts, and MMP-2 activity in renal transplant fibroblasts. MMP-1 activity was also decreased by cyclosporin A in renal transplant fibroblasts, but marginally. Azithromycin enhanced MMP-1 and MMP-2 activities in cyclosporin A-treated renal transplant fibroblasts and normal fibroblasts. Azithromycin lowered cyclosporin A-induced collagen accumulation to control levels in renal transplant fibroblasts. Furthermore, analysis of RT-PCR data indicated that azithromycin inhibited cyclosporin A-induced mRNA levels in type I collagen, and reversed the reduction in MMP-2 mRNA levels by cyclosporin A. However, MMP-1, TIMP-1, and TIMP-2 mRNA levels were not influenced by azithromycin. Although considerable attention has been focused on the role of MMP-1 as an interstitial collagenase in CIGO, previous studies have shown that MMP-2 is a cell-surface-associated type I collagen-degrading MMP (Emonard et al., 1992; Aimes and Quigley, 1995) and plays a key role in ECM remodeling (Deryugina et al., 1998). Actually, MMP-2 showed its collagenolytic activity on the gel containing type I collagen.
In conclusion, azithromycin may improve the symptoms of CIGO by blocking cyclosporin A-induced cell proliferation and collagen accumulation, and by activating MMP-2 rather than MMP-1 in gingival fibroblasts of persons with cyclosporine A-induced gingival overgrowth.
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ACKNOWLEDGMENTS
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This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (01-PJ5-PG3-20507-0020). We thank Pfizer Incorporation for providing azithromycin.
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FOOTNOTES
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5 authors contributing equally to this work 
Received for publication January 23, 2008.
Revision received June 11, 2008.
Accepted for publication July 31, 2008.
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Journal of Dental Research, Vol. 87, No. 11,
1075-1079 (2008)
DOI: 10.1177/154405910808701110
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ABSTRACT
INTRODUCTION