Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARγ activation in human gingival fibroblasts
© Stewart et al; licensee BioMed Central Ltd. 2007
Received: 26 July 2006
Accepted: 23 February 2007
Published: 23 February 2007
Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Activators of peroxisome proliferator-activated receptor-γ (PPARγ) have been shown to inhibit cytokine induced expression of MMPs in other cell types, and IL-4 has been shown to activate PPARγ by stimulating production of ligands through the lipoxygenase pathway. It has been suggested that PPARγ may inhibit expression of MMPs by competing with transcription factor AP-1 for binding to a putative composite binding element in the promoters. The objective of this study was to determine whether the suppressive effects of IL-4 on the IL-1 induced expression of MMP-3 involve activation of lipoxygenase and/or PPARγ.
Western blotting revealed the presence of PPARγ in nuclear extract of HGF. IL-1 induced binding of nuclear extract to the putative composite PPRE/AP-1 site was diminished in the presence of pioglitazone, but there was no evidence of any change in the composition of the retarded complexes, and no evidence of PPARγ binding to this site. Nordihydroguaiaretic acid (NDGA), a non-selective lipoxygenase inhibitor, and MK886, a specific inhibitor of 5-lipoxygenase, induced MMP-3 expression synergistically with IL-1. However IL-4 was still able to inhibit MMP-3 expression in the presence of NDGA or MK886 and IL-1. Activation of PPARγ with pioglitazone not only failed to inhibit IL-1 induced expression of MMP-3 mRNA, but rather super-induced MMP-3 in the presence of IL-1. PPARγ antagonist GW9662 failed to abolish the suppressive effects of IL-4. Another PPARγ activator, 15-deoxy-Delta12,14prostaglandin J2 (15dPGJ2), also super-induced MMP-3 mRNA, and this was due at least in part to increased transcription.
IL-4 suppression of IL-1-induced MMP-3 expression in HGF is independent of lipoxygenase activity and activation of PPARγ. Super-induction of MMP-3 by pioglitazone may have important implications for patients using pioglitazone to treat type II diabetes in the presence of chronic inflammation.
MMP-3 (stromelysin-1) is a metalloproteinase with broad substrate specificity, degrading proteoglycan, laminin, fibronectin, and the non-fibrillar collagens . Perhaps equally important, it is also capable of activating other pro-MMP's, including MMP-1, -8, -9 and -13 [2–4], of inactivating plasminogen activator inhibitor I , and of cleaving E-cadherin  and FasL . MMP-3 is produced by gingival and synovial fibroblasts, chondrocytes, macrophages, neutrophils, and endothelial cells in response to inflammatory cytokines and mitogens. In periodontitis, MMP-3 is present at increased levels in active disease sites compared to inactive or healthy sites [8–11], and the levels are correlated with clinical parameters and associated with progression of the disease . A similar situation exists in rheumatoid arthritis . Studies of the effects of a promoter polymorphism that affects protein expression has shown that individuals with the high expressing 5A/5A genotype are at increased risk for aneurysms and myocardial infarctions [13–15], while those with the lower expressing 6A/6A genotype show a faster progression of atherosclerosis [15, 16]. Taken together, these studies suggest that regulation of MMP-3 levels is important for the maintenance of health, and that either too much or too little can have detrimental effects.
Chronic inflammation in rheumatoid arthritis and periodontitis is characterized by increased levels of IL-1β, TNFα and prostaglandin E2 (PGE2), which contribute to destruction of joints and alveolar bone in part through increased production of matrix metalloproteinases (MMPs) [17–20]. In addition, there is a relative absence of IL-4-producing T cells at sites of inflammation [12, 21–25]. This imbalance is progressive, with decreasing levels of IL-4 correlated with loss of collagen and with increasing clinical severity . In addition, polymorphisms in the IL-4 promoter and intron that are associated with decreased serum levels of IL-4 are also associated with increased susceptibility to early onset periodontitis . It has been suggested that correcting this cytokine imbalance in chronic inflammatory conditions might be therapeutic. In fact, adenoviral transfer of IL-4 has been shown to be protective against cartilage degradation induced by injection of rheumatoid arthritis synovial tissue into joints of SCID mice  and against collagen-induced arthritis .
IL-4 has been shown to inhibit the IL-1 induction of MMP-3 expression in human conjunctival fibroblasts , skin fibroblasts  and articular chondrocytes [32, 33], as well as in synovial fibroblast cultures established from patients with osteoarthritis  and gingival fibroblast (HGF) cultures established from patients with periodontitis . The mechanism of the inhibition of MMP-3 by IL-4 in HGF was not determined, although PGE2 was not involved, and DNA binding of transcription factors AP-1 and NF-κB to their consensus sequences was not inhibited .
Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor super-family. It plays an important role in adipogenesis and insulin sensitization and has also been shown to have a number of anti-inflammatory effects . IL-4 has been shown to activate PPARγ in macrophages by increasing the activity of 15-lipoxygenase, leading to increased production of ligands [37–39]. PPARγ ligands and agonists have been shown to inhibit production of MMP-3 [40, 41], and to prevent MMP-mediated tissue destruction in animal models of inflammation, including arthritis [42, 43] and periodontitis .
A recent study by Francois, et al.  identified a composite element in the rabbit MMP-1 promoter that exhibited mutually exclusive binding of PPARγ or AP-1 and was responsible for reduced gene expression in the presence of PPARγ agonist rosiglitazone in chondrocytes. The authors reported that computer-based analysis of the human MMP-1 and MMP-3 promoter sequences revealed similar putative composite elements overlapping the well-studied AP-1 sites in each gene. The present study was undertaken to determine whether there is a functional composite PPRE/AP-1 site in the MMP-3 promoter, and if so, whether it is involved in IL-4 suppression of IL-1 induced expression of MMP-3 in HGF. Results show that there is no binding of PPARγ to this site in HGF, and that the suppressive effects of IL-4 are independent of lipoxygenase activity and PPARγ. Surprisingly, a 5-lipoxygenase inhibitor and a PPARγ activator both super-induce MMP-3 in the presence of IL-1.
PPAR-γ is present in HGF nuclear extract
Pioglitazone and IL-4 reduce AP-1 binding to the putative PPRE/AP-1 site, but do not change the composition of the complexes
Inhibition of lipoxygenase fails to inhibit MMP-3 expression
Activation of PPARγ with Pioglitazone or 15dPGJ2 does not inhibit IL-1 induced expression of MMP-3 mRNA in HGF
Results shown here demonstrate that there is no competition between PPARγ and AP-1 for binding to the MMP-3 promoter, and that IL-4 suppression of IL-1-induced expression of MMP-3 in HGF does not involve activation of lipoxygenase enzymes and/or PPARγ. However, the fact that inhibitors of lipoxygenase and an activator of PPARγ both resulted in super-induction of MMP-3 in the presence of IL-1 suggests that these factors may play a role in MMP-3 gene regulation.
Previous studies with the AP-1 site failed to detect any changes in DNA binding in cells treated with IL-1 plus IL-4 as compared to IL-1 alone [34, 35]. Use of a larger probe containing the putative PPRE/AP-1 composite site did show decreased intensity of retarded bands in the presence of IL-4 (Figure 2). However there was no change in the migration of the retarded bands as one would expect if PPARγ were binding to the site in competition with AP-1, and a PPARγ specific antibody failed to supershift the bands. IL-4 has been reported to stimulate expression of JunB in peripheral blood monocytes from patients with atopic dermatitis . Since JunB is less transcriptionally active than c-Jun [49, 50], such a shift in the composition of AP-1 dimers would be expected to decrease transcription of at least some AP-1 dependent genes. Use of antisera against phosphorylated (active) c-Jun and Jun B suggest that IL-4 is not interfering with activation of c-Jun, nor is it changing AP-1 activity by causing the formation of less active dimers containing JunB. Taken together, these data demonstrate that IL-4 inhibition of MMP-3 expression cannot be explained by competition for binding to the AP-1 site or by changes in the composition of the AP-1 dimer.
Activation of PPARγ has been shown to inhibit cytokine stimulated gene expression in a number of ways, including inhibition of NF-κB and AP-1 activity through competition for limiting amounts of transcriptional coactivators [46, 47]. Furthermore, IL-4 has been shown to activate PPARγ by stimulating the production of ligands through the lipoxygenase pathway [37–39] and in at least one case, through the production of alternative ligands .
The fact that IL-4 could still inhibit MMP-3 expression in the presence of NDGA or MK886 suggests that the mechanism of IL-4 inhibition does not require activation of lipoxygenase enzymes. Super-induction of IL-1 stimulated MMP-3 expression by NDGA was surprising in light of the fact that NDGA is known to inhibit AP-1 activity  and it has been shown to inhibit expression of MMP-3 in response to IL-17 . Since pioglitazone also resulted in stimulation of MMP-3 expression while inhibiting AP-1 binding (Figures 2, 5), it is clear that other pathways are more important than AP-1 in this context.
As reported earlier , IL-4 failed to inhibit IL-1 induction of MMP-1. Although NDGA induced MMP-1 over control levels, it failed to super-induce MMP-1 with IL-1 as it did with MMP-3. These results represent another addition to a growing list of situations in which these two genes are not co-ordinately regulated. In one instance, Otani et al  showed induction of MMP-3, but not MMP-1 in the presence of cycloheximide. They suggested that cycloheximide might be inducing MMP-3 expression by preventing translation of a "labile repressor". It is interesting to note as well that the increased transcription of the MMP-3 promoter construct was observed only with the construct containing the 5A polymorphism and not in the construct containing the 6A polymorphism (data not shown). Since this polymorphic site has been shown to act as a repressor element in normal fibroblasts [16, 54], it is tempting to speculate that these reagents are affecting the binding or activity of transcription factor(s) binding to this site in order to relieve the repression. Further experiments are needed to address these questions.
Interactions between the cyclooxygenase, lipoxygenase and PPAR pathways are overlapping and complex. Arachidonic acid is a common substrate for both cyclooxygenase and lipoxygenase enzymes. Expression of 15- and 5-lipoxygenase enzymes is often reciprocal [55, 56]. Activation of PPARγ by troglitazone has been shown to inhibit expression of 5-lipoxygenase in rheumatoid arthritis synovial fibroblasts , lipoxygenase inhibitors can activate PPARγ in breast cancer cells  and COX-2 expression in macrophages has been postulated to be regulated by negative feedback mediated by PPARγ .
One potential explanation for the unexpected effects of NDGA and MK886, therefore, is that inhibition of lipoxygenase enzymes leads to an excess of arachidonic acid, which can then be converted to prostaglandins by cyclooxygenases. If pioglitazone and/or 15d PGJ2 caused a down-regulation of 5-lipoxygenase expression and/or activity, then they too could result in increased levels of arachidonic acid and increased production of prostaglandins.
This is not straight-forward however, since the effects of PGE2 on MMP-3 expression are variable, ranging from induction [60, 61], to inhibition [62–64], to no effect [30, 65]. A particularly interesting study by Rowanpura et al. , showed that the effects of PGE2 on IL-1 stimulated expression of MMP-3 differ in HGF derived from healthy tissue as opposed to HGF derived from patients with severe periodontitis. In HGF from healthy donors, PGE2 inhibited the IL-1 induction of MMP-3, whereas in diseased tissue, it resulted in further stimulation. This difference was shown to result from a change in PGE2 receptors, from EP2 and EP4 in healthy tissue to predominantly EP1 in diseased tissue.
Since our HGF were derived from patients with periodontitis, it is possible that addition of NDGA, MK886 and/or pioglitazxone resulted indirectly in increased production of PGE2, which caused super-induction of MMP-3 as described by Ruwanpura, et al. . It is important to note that in previous studies using similarly derived HGF, addition of exogenous PGE2 failed to abrogate the suppressive effects of IL-4 on MMP-3 expression , but the effects of exogenous PGE2 alone or together with IL-1 were not tested. In the present study, there was some variation in the magnitude of responses, but the responses themselves were qualitatively consistent among cultures established from different individuals (n = 7 for NDGA, n = 5 for MK886, n = 3 for pioglitazone, n = 6 for 15d PGJ2 experiments).
Aside from demonstrating that PPARγ is not involved in the effects of IL-4 on MMP-3 expression, the failure of pioglitazone and 15dPGJ2 to inhibit MMP-3 expression (Figures 5 and 6) was surprising because other studies have shown inhibition of MMP-3 expression by activators of PPARγ [40, 41]. The most obvious explanation for the super-induction would be the presence of a PPRE in the MMP-3 promoter. Computer analysis of the promoter sequence [Genomatix, ] failed to identify any PPRE. However, a recent study found that of the 73 known functional PPRE, only 2 conformed to the DR1 consensus, and 8% of them had 5 or more mismatches . Therefore, this possibility cannot be excluded without further study.
The possibility of PPARγ-independent effects of pioglitazone and 15dPGJ2 also cannot be ruled out. 15dPGJ2 has been shown to have several effects independent of PPAR, including inhibition of NFκB . Pioglitazone has been shown to up-regulate AMP-activated kinase in rat muscle and in NIH3T3 cells) and to increase LPS stimulated production of PGE2 at high doses . Aizawa et al.  showed that pioglitazone increased the IL-1 induced expression of inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells (VSMCs) independent of PPARγ.
Both NDGA and pioglitazone have anti-oxidant properties which have been linked to their ability to inhibit the activity of redox sensitive transcription factor NF-κB [43, 73, 74]. NF-κB has been implicated in several studies to be involved in up-regulation of MMP-3 in inflammation [75–77], but more recent studies have shown that NF-κB binds to a polymorphic repressor element in the MMP-3 promoter in competition with zinc-binding protein 89 (ZBP-89) to limit IL-1 induced transcription , unpublished]. Further study is needed to determine more precisely the direct and indirect roles of NF-κB in MMP-3 regulation and how these roles are affected by any alterations in eicosanoid synthesis or actions that might take place in the context of chronic inflammation.
In summary, these data demonstrate that the ability of IL-4 to suppress IL-1 induced expression of MMP-3 does not involve activation of PPARγ and/or lipoxygenase activity in HGF. However, the fact that lipoxygenase inhibition and PPARγ activation were both able to super-induce MMP-3 mRNA suggests that these pathways are involved in MMP-3 gene regulation. These results also suggest that treatment with drugs that target these pathways in the context of chronic inflammation could have some unpredicted effects. Further study is necessary to determine how these effects are mediated and to what extent they are relevant to the disease process(es).
Human gingival tissue from patients undergoing periodontal surgery was obtained from Howard M. Sobel, D.D.S. and Kevan S. Green, D.M.D. of Sobel Periodontal Associates, P.C. The tissue was processed by enzymatic dispersion to produce primary cultures. Cells were maintained in Eagle's Minimal Essential Medium (EMEM) supplemented with 10% fetal bovine serum and antibiotic/antimycotic (penicillin, streptomycin, amphotericin; Gibco BRL, Grand Island, NY). Cells between passages 3 and 5 were used for experiments. COS-1 cells were obtained from ATCC and maintained as suggested.
RNA isolation and real-time PCR
Cells were serum-deprived for 16 hours in serum-free EMEM supplemented with 10% ITS (insulin, transferrin, sodium selenite; Sigma, St. Louis, MO) prior to the addition of NDGA, MK886, pioglitazone, 15dPGJ2 or GW9962 (Sigma) in the indicated doses. After one hour incubation, 10 ng IL-1β/ml (DuPont-Merck Corp., Wilmington, DE) was added, in the presence or absence of 10 ng/ml IL-4 (Gibco BRL, Grand Island, NY). Total RNA was isolated 6 or 12 hours later using the RNAqueous-4PCR kit (Ambion, Austin, TX) according to manufacture's instructions and reverse transcribed into cDNA using the High Capacity cDNA Archive Kit (Applied Biosystem, Foster City, CA) and Thermal Cycler Genius. Real Time PCR reactions were consisted of 2.5 μl of cDNA, 12.5 μl of Taqman Universal PCR master mix (Applied Biosystem), 8.75 μl H2O and 1.25 μl probes (stromylsin-MMP-3, collagenase I-MMP-1, Glyceraldehyde-3-Phosphate Dehydrogenase-GAPDH; Applied Biosystem) or 2 μl of cDNA, 6.8 μl of H2O, 10 μl of the Premix Ex Taq™ (master mix and 0.4 μl ROX Reference Dye; TAKARA, Madison, WI) and 0.8 μl probes. Real Time PCR analysis was done using the Applied Biosystem 7500 Real Time PCR system. Reactions were done in triplicate and results were normalized to GAPDH.
Nuclear extract isolation and gelshift assays
Nuclear extracts were isolated according to the method of Schreiber et al.  and quantified in mini-Bradford assays (Pierce, Rockford, IL). Synthetic oligonucleotides corresponding to the putative composite PPRE/AP-1 site (5' GAAAGCAAGGTGAGTCAAGCTG 3')  were labelled by T4 polynucleotide kinase in the presence of γ32P-ATP. Binding reactions contained 5 μg protein, 20 mM Hepes-OH pH 7, 50 mM NaCl, 0.2 M EDTA, 5% glycerol, 4 μg dIdC and 10,000 cpm probe.
Fifteen μg nuclear extract were separated on 10% SDS-polyacrylamide gels. Proteins were transferred to Immobilon-P Transfer Membrane (Millipore) and the membrane was blocked overnight with Super Block blocking buffer (Pierce). The blot was then incubated with anti-PPAR-γ antibody (Santa Cruz) diluted 1:1000 in Super Block for one hour at room temperature. After washing three times in TBST (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.5% Tween 20), the blots were incubated with a goat anti-rabbit secondary antibody conjugated to horseradish peroxidase (Pierce) for one hour. After three more washes in TBST, the blot was incubated with SuperSignal West Pico Chemiluminescent Substrate (Pierce) and exposed to X-ray film.
A luciferase reporter construct containing 2300 bp of the MMP-3 5' flanking region and the 5T promoter polymorphism has been described previously . Transient transfections were performed in triplicate using Lipofectamine Plus (GibcoBRL), with SV-βgal as a control for transfection efficiency. Cells were harvested 36 hours later.
Determination of MMP-3 protein levels
MP-3 protein levels were quantitated by ELISA (Calbiochem, Darmstadt, Germany) in conditioned media of human gingival fibroblasts (HGF) that were untreated, treated with 10 ng IL-1/ml alone or treated with both 10 ng IL-1/ml and 0.1, 1.0 or 10 μM MK886 for 24 hours.
The authors would like to thank Bill Laidlaw for technical assistance, and Howard M. Sobel, D.D.S. and Kevan S. Greene, D.M.D. for providing gingival tissue samples. This work was funded by grant R15DE16277 from the NIH/NIDCR to RCB.
- Parsons SL, Watson SA, Brown PD, Collins HM, Steele RJ: Matrix metalloproteinases. Br J Surg. 1997, 84: 160-166. 10.1002/bjs.1800840206View ArticlePubMedGoogle Scholar
- Knauper V, Wilhelm SM, Seperack PK, DeClerck YA, Langley KE, Osthues A, Tschesche H: Direct activation of human neutrophil procollagenase by recombinant stromelysin. Biochem J. 1993, 295: 581-586.PubMed CentralView ArticlePubMedGoogle Scholar
- Murphy G, Cockett MI, Stephens PE, Smith BJ, Docherty AJ: Stromelysin is an activator of procollagenase. A study with natural and recombinant enzymes. Biochem J. 1987, 248: 265-268.PubMed CentralView ArticlePubMedGoogle Scholar
- Ogata Y, Enghild JJ, Nagase H: Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem. 1992, 267: 3581-3584.PubMedGoogle Scholar
- Lijnen HR, Arza B, Van Hoef B, Collen D, Declerck PJ: Inactivation of plasminogen activator inhibitor-1 by specific proteolysis with stromelysin-1 (MMP-3). J Biol Chem. 2000, 275: 37645-37650. 10.1074/jbc.M006475200View ArticlePubMedGoogle Scholar
- Noe V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM, Mareel M: Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci. 2001, 114: 111-118.PubMedGoogle Scholar
- Matsuno H, Yudoh K, Watanabe Y, Nakazawa F, Aono H, Kimura T: Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand. J Rheumatol. 2001, 28: 22-28.PubMedGoogle Scholar
- Aiba T, Akeno N, Kawane T, Okamoto H, Horiuchi N: Matrix metalloproteinases-1 and -8 and TIMP-1 mRNA levels in normal and diseased human gingivae. Eur J Oral Sci. 1996, 104: 562-569.View ArticlePubMedGoogle Scholar
- Haerian A, Adonogianaki E, Mooney J, Docherty JP, Kinane DF: Gingival crevicular stromelysin, collagenase and tissue inhibitor of metalloproteinases levels in healthy and diseased sites. J Clin Periodontol. 1995, 22: 505-509. 10.1111/j.1600-051X.1995.tb00797.xView ArticlePubMedGoogle Scholar
- Reynolds JJ, Hembry RM, Meikle MC: Connective tissue degradation in health and periodontal disease and the roles of matrix metalloproteinases and their natural inhibitors. Adv Dent Res. 1994, 8: 312-319.PubMedGoogle Scholar
- Alpagot T, Bell C, Lundergan W, Chambers DW, Rudin R: Longitudinal evaluation of GCF MMP-3 and TIMP-1 levels as prognostic factors for progression of periodontitis. J Clin Periodontol. 2001, 28: 353-359. 10.1034/j.1600-051x.2001.028004353.xView ArticlePubMedGoogle Scholar
- Moissec P, Naviliat M, D’Angeac AD, Sany J, Banchereau J: Low levels of interleukin-4 and high level of transforming growth factor b in rheumatoid arthritis. Arthritis Rheum. 1990, 33: 1180-1187.View ArticleGoogle Scholar
- Yoon S, Tromp G, Vongpunsawad S, Ronkainen A, Juvonen T, Kuivaniemi H: Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms. Biochem Biophys Res Commun. 1999, 265: 563-568. 10.1006/bbrc.1999.1721View ArticlePubMedGoogle Scholar
- Lamblin N, Bauters C, Hermant X, Lablanche JM, Helbecque N, Amouyel P: Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease. J Am Coll Cardiol. 2002, 40: 43-48. 10.1016/S0735-1097(02)01909-5View ArticlePubMedGoogle Scholar
- Beyzade S, Zhang S, Wong YK, Day IN, Eriksson P, Ye S: Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. J Am Coll Cardiol. 2003, 41: 2130-2137. 10.1016/S0735-1097(03)00482-0View ArticlePubMedGoogle Scholar
- Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM: Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J. 1995, 73: 209-215.PubMed CentralView ArticlePubMedGoogle Scholar
- Honig J, Rordorf-Adam C, Siegmund C, Wiedemann W, Erard F: Increased interleukin-1 beta (IL-1 beta) concentration in gingival tissue from periodontitis patients. J Periodontal Res. 1989, 24: 362-367. 10.1111/j.1600-0765.1989.tb00883.xView ArticlePubMedGoogle Scholar
- Stashenko P, Fujiyoshi P, Obernesser MS, Prostak L, Haffajee AD, Socransky SS: Levels of interleukin 1 beta in tissue from sites of active periodontal disease. J Clin Periodontol. 1991, 18: 548-554. 10.1111/j.1600-051X.1991.tb00088.xView ArticlePubMedGoogle Scholar
- Cheung NT, Dawes PT, Poulton KV, Ollier WE, Taylor DJ, Mattey DL: High serum levels of pro-matrix metalloproteinase-3 are associated with greater radiographic damage and the presence of the shared epitope in patients with rheumatoid arthritis. J Rheumatol. 2000, 27: 882-887.PubMedGoogle Scholar
- van den Berg WB, Bresnihan B: Pathogenesis of joint damage in rheumatoid arthritis: evidence of a dominant role for interleukin-I. Baillieres Best Pract Res Clin Rheumatol. 1999, 13: 577-597. 10.1053/berh.1999.0047View ArticlePubMedGoogle Scholar
- Shapira L, van Dyke TE, Hart TC: A localized absence of interleukin-4 triggers periodontal disease activity: a novel hypothesis. Med Hypotheses. 1992, 39: 319-322. 10.1016/0306-9877(92)90056-IView ArticlePubMedGoogle Scholar
- Ukai T, Mori Y, Onoyama M, Hara Y: Immunohistological study of interferon-gamma- and interleukin-4-bearing cells in human periodontitis gingiva. Arch Oral Biol. 2001, 46: 901-908. 10.1016/S0003-9969(01)00057-7View ArticlePubMedGoogle Scholar
- Yamamoto M, Fujihashi K, Hiroi T, McGhee JR, Van Dyke TE, Kiyono H: Molecular and cellular mechanisms for periodontal diseases: role of Th1 and Th2 type cytokines in induction of mucosal inflammation. J Periodontal Res. 1997, 32: 115-119. 10.1111/j.1600-0765.1997.tb01391.xView ArticlePubMedGoogle Scholar
- van der Graaff WL, Prins AP, Niers TM, Dijkmans BA, van Lier RA: Quantitation of interferon gamma- and interleukin-4-producing T cells in synovial fluid and peripheral blood of arthritis patients. Rheumatology (Oxford). 1999, 38: 214-220. 10.1093/rheumatology/38.3.214View ArticleGoogle Scholar
- Dolhain RJ, van der Heiden AN, ter Haar NT, Breedveld FC, Miltenberg AM: Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1961-1969. 10.1002/art.1780391204View ArticlePubMedGoogle Scholar
- Ejeil AL, Gaultier F, Igondjo-Tchen S, Senni K, Pellat B, Godeau G, Gogly B: Are cytokines linked to collagen breakdown during periodontal disease progression?. J Periodontol. 2003, 74: 196-201. 10.1902/jop.2003.74.2.196View ArticlePubMedGoogle Scholar
- Michel J, Gonzales JR, Wunderlich D, Diete A, Herrmann JM, Meyle J: Interleukin-4 polymorphisms in early onset periodontitis. J Clin Periodontol. 2001, 28: 483-488. 10.1034/j.1600-051x.2001.028005483.xView ArticlePubMedGoogle Scholar
- Jorgensen C, Apparailly F, Couret I, Canovas F, Jacquet C, Sany J: Interleukin-4 and interleukin-10 are chondroprotective and decrease mononuclear cell recruitment in human rheumatoid synovium in vivo. Immunology. 1998, 93: 518-523. 10.1046/j.1365-2567.1998.00457.xPubMed CentralView ArticlePubMedGoogle Scholar
- Lubberts E, Joosten LA, van Den Bersselaar L, Helsen MM, Bakker AC, van Meurs JB, Graham FL, Richards CD, van Den Berg WB: Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction. J Immunol. 1999, 163: 4546-4556.PubMedGoogle Scholar
- Fukuda K, Fujitsu Y, Kumagai N, Nishida T: Inhibition of matrix metalloproteinase-3 synthesis in human conjunctival fibroblasts by interleukin-4 or interleukin-13. Invest Ophthalmol Vis Sci. 2006, 47: 2857-2864. 10.1167/iovs.05-1261View ArticlePubMedGoogle Scholar
- Prontera C, Crescenzi G, Rotilio D: Inhibition by Interleukin-4 of stromelysin expression in human skin fibroblasts: role of PKC. Exp Cell Res. 1996, 224: 183-188. 10.1006/excr.1996.0126View ArticlePubMedGoogle Scholar
- Shingu M, Miyauchi S, Nagai Y, Yasutake C, Horie K: The role of IL-4 and IL-6 in IL-1-dependent cartilage matrix degradation. Br J Rheumatol. 1995, 34: 101-106. 10.1093/rheumatology/34.2.101View ArticlePubMedGoogle Scholar
- Nemoto O, Yamada H, Kikuchi T, Shinmei M, Obata K, Sato H, Seiki M, Shimmei M: Suppression of matrix metalloproteinase-3 synthesis by interleukin-4 in human articular chondrocytes. J Rheumatol. 1997, 24: 1774-1779.PubMedGoogle Scholar
- Borghaei RC, Rawlings PL, Mochan E: Interleukin-4 suppression of interleukin-1-induced transcription of collagenase (MMP-1) and stromelysin 1 (MMP-3) in human synovial fibroblasts. Arthritis Rheum. 1998, 41: 1398-1406. 10.1002/1529-0131(199808)41:8<1398::AID-ART8>3.0.CO;2-BPubMed CentralView ArticlePubMedGoogle Scholar
- Jenkins K, Javadi M, Borghaei RC: Interleukin-4 suppresses interleukin-1-induced expression of matrix metalloproteinase-3 in human gingival fibroblasts. J Periodontol. 2004, 75: 267-275. 10.1902/jop.2004.75.2.283.View ArticleGoogle Scholar
- Lehrke M, Lazar MA: The many faces of PPARgamma. Cell. 2005, 123: 993-999. 10.1016/j.cell.2005.11.026View ArticlePubMedGoogle Scholar
- Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK: Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature. 1999, 400: 378-382. 10.1038/22572View ArticlePubMedGoogle Scholar
- Ricote M, Welch JS, Glass CK: Regulation of macrophage gene expression by the peroxisome proliferator-activated receptor-gamma. Horm Res. 2000, 54: 275-280. 10.1159/000053271View ArticlePubMedGoogle Scholar
- Bendixen AC, Shevde NK, Dienger KM, Willson TM, Funk CD, Pike JW: IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1. Proc Natl Acad Sci U S A. 2001, 98: 2443-2448. 10.1073/pnas.041493198PubMed CentralView ArticlePubMedGoogle Scholar
- Sabatini M, Bardiot A, Lesur C, Moulharat N, Thomas M, Richard I, Fradin A: Effects of agonists of peroxisome proliferator-activated receptor gamma on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro. Osteoarthritis Cartilage. 2002, 10: 673-679. 10.1053/joca.2002.0827View ArticlePubMedGoogle Scholar
- Yamasaki S, Nakashima T, Kawakami A, Miyashita T, Ida H, Migita K, Nakata K, Eguchi K: Functional changes in rheumatoid fibroblast-like synovial cells through activation of peroxisome proliferator-activated receptor gamma-mediated signalling pathway. Clin Exp Immunol. 2002, 129: 379-384. 10.1046/j.1365-2249.2002.01876.xPubMed CentralView ArticlePubMedGoogle Scholar
- Kobayashi T, Notoya K, Naito T, Unno S, Nakamura A, Martel-Pelletier J, Pelletier JP: Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, reduces the progression of experimental osteoarthritis in guinea pigs. Arthritis Rheum. 2005, 52: 479-487. 10.1002/art.20792View ArticlePubMedGoogle Scholar
- Shiojiri T, Wada K, Nakajima A, Katayama K, Shibuya A, Kudo C, Kadowaki T, Mayumi T, Yura Y, Kamisaki Y: PPAR gamma ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice. Eur J Pharmacol. 2002, 448: 231-238. 10.1016/S0014-2999(02)01946-5View ArticlePubMedGoogle Scholar
- Di Paola R, Mazzon E, Maiere D, Zito D, Britti D, De Majo M, Genovese T, Cuzzocrea S: Rosiglitazone reduces the evolution of experimental periodontitis in the rat. J Dent Res. 2006, 85: 156-161.View ArticlePubMedGoogle Scholar
- Francois M, Richette P, Tsagris L, Raymondjean M, Fulchignoni-Lataud MC, Forest C, Savouret JF, Corvol MT: Peroxisome proliferator-activated receptor-gamma down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element. J Biol Chem. 2004, 279: 28411-28418. 10.1074/jbc.M312708200View ArticlePubMedGoogle Scholar
- Abdelrahman M, Sivarajah A, Thiemermann C: Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock. Cardiovasc Res. 2005, 65: 772-781. 10.1016/j.cardiores.2004.12.008View ArticlePubMedGoogle Scholar
- Yki-Jarvinen H: Thiazolidinediones. N Engl J Med. 2004, 351: 1106-1118. 10.1056/NEJMra041001View ArticlePubMedGoogle Scholar
- Yamazaki F, Aragane Y, Maeda A, Matsushita K, Ueno K, Yudate T, Kawada A, Tezuka T: Overactivation of IL-4-induced activator protein-1 in atopic dermatitis. J Dermatol Sci. 2002, 28: 227-233. 10.1016/S0923-1811(01)00171-2View ArticlePubMedGoogle Scholar
- Chiu R, Angel P, Karin M: Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell. 1989, 59: 979-986. 10.1016/0092-8674(89)90754-XView ArticlePubMedGoogle Scholar
- Schutte J, Viallet J, Nau M, Segal S, Fedorko J, Minna J: jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun. Cell. 1989, 59: 987-997. 10.1016/0092-8674(89)90755-1View ArticlePubMedGoogle Scholar
- Park S, Lee DK, Yang CH: Inhibition of fos-jun-DNA complex formation by dihydroguaiaretic acid and in vitro cytotoxic effects on cancer cells. Cancer Lett. 1998, 127: 23-28. 10.1016/S0304-3835(97)00543-0View ArticlePubMedGoogle Scholar
- Sylvester J, Liacini A, Li WQ, Zafarullah M: Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes. Cell Signal. 2004, 16: 469-476. 10.1016/j.cellsig.2003.09.008View ArticlePubMedGoogle Scholar
- Otani Y, Quinones S, Saus J, Kurkinen M, Harris Jr. ED: Cycloheximide induces styromelysin mRNA in cultured human fibroblasts. Eur J Biochem. 1990, 192: 75-79. 10.1111/j.1432-1033.1990.tb19197.xView ArticlePubMedGoogle Scholar
- Borghaei RC, Rawlings PL, Javadi M, Woloshin J: NF-kappaB binds to a polymorphic repressor element in the MMP-3 promoter. Biochem Biophys Res Commun. 2004, 316: 182-188. 10.1016/j.bbrc.2004.02.030View ArticlePubMedGoogle Scholar
- Sun D, Funk CD: Disruption of 12/15-lipoxygenase expression in peritoneal macrophages. Enhanced utilization of the 5-lipoxygenase pathway and diminished oxidation of low density lipoprotein. J Biol Chem. 1996, 271: 24055-24062. 10.1074/jbc.271.39.24055View ArticlePubMedGoogle Scholar
- Spanbroek R, Hildner M, Kohler A, Muller A, Zintl F, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ: IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression. Proc Natl Acad Sci U S A. 2001, 98: 5152-5157. 10.1073/pnas.091076998PubMed CentralView ArticlePubMedGoogle Scholar
- Tsubouchi Y, Kawahito Y, Kohno M, Inoue K, Hla T, Sano H: Feedback control of the arachidonate cascade in rheumatoid synoviocytes by 15-deoxy-Delta(12, 14)-prostaglandin J2. Biochem Biophys Res Commun. 2001, 283: 750-755. 10.1006/bbrc.2001.4847View ArticlePubMedGoogle Scholar
- Avis I, Martinez A, Tauler J, Zudaire E, Mayburd A, Abu-Ghazaleh R, Ondrey F, Mulshine JL: Inhibitors of the arachidonic acid pathway and peroxisome proliferator-activated receptor ligands have superadditive effects on lung cancer growth inhibition. Cancer Res. 2005, 65: 4181-4190. 10.1158/0008-5472.CAN-04-3441View ArticlePubMedGoogle Scholar
- Inoue H, Tanabe T, Umesono K: Feedback control of cyclooxygenase-2 expression through PPARgamma. J Biol Chem. 2000, 275: 28028-28032.PubMedGoogle Scholar
- Thampatty BP, Im HJ, Wang JH: Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts. Gene. 2006, 372: 103-109. 10.1016/j.gene.2005.12.013PubMed CentralView ArticlePubMedGoogle Scholar
- Domeij H, Yucel-Lindberg T, Modeer T: Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts. Eur J Oral Sci. 2002, 110: 302-306. 10.1034/j.1600-0722.2002.21247.xView ArticlePubMedGoogle Scholar
- Case JP, Lafyatis R, Kumkumian GK, Remmers EF, Wilder RL: IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway. J Immunol. 1990, 145: 3755-3761.PubMedGoogle Scholar
- DiBattista JA, Martel-Pelletier J, Fujimoto N, Obata K, Zafarullah M, Pelletier JP: Prostaglandins E2 and E1 inhibit cytokine-induced metalloprotease expression in human synovial fibroblasts. Mediation by cyclic-AMP signalling pathway. Lab Invest. 1994, 71: 270-278.PubMedGoogle Scholar
- Yan M, Noguchi K, Ruwanpura SM, Ishikawa I: Cyclooxygenase-2-dependent prostaglandin (PG) E2 downregulates matrix metalloproteinase-3 production via EP2/EP4 subtypes of PGE2 receptors in human periodontal ligament cells stimulated with interleukin-1alpha. J Periodontol. 2005, 76: 929-935. 10.1902/jop.2005.76.6.929View ArticlePubMedGoogle Scholar
- Mauviel A, Halcin C, Vasiloudes P, Parks WC, Kurkinen M, Uitto J: Uncoordinate regulation of collagenase, stromelysin, and tissue inhibitor of metalloproteinases genes by prostaglandin E2: selective enhancement of collagenase gene expression in human dermal fibroblasts in culture. J Cell Biochem. 1994, 54: 465-472. 10.1002/jcb.240540413View ArticlePubMedGoogle Scholar
- Ruwanpura SM, Noguchi K, Ishikawa I: Prostaglandin E2 regulates interleukin-1beta-induced matrix metalloproteinase-3 production in human gingival fibroblasts. J Dent Res. 2004, 83: 260-265.View ArticlePubMedGoogle Scholar
- Genomatix. http://www.genomatix.de/
- Lemay DG, Hwang DH: Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics. J Lipid Res. 2006Google Scholar
- Giri S, Rattan R, Singh AK, Singh I: The 15-deoxy-delta12, 14-prostaglandin J2 inhibits the inflammatory response in primary rat astrocytes via down-regulating multiple steps in phosphatidylinositol 3-kinase-Akt-NF-kappaB-p300 pathway independent of peroxisome proliferator-activated receptor gamma. J Immunol. 2004, 173: 5196-5208.View ArticlePubMedGoogle Scholar
- Lebrasseur NK, Kelly M, Tsao TS, Farmer SR, Saha AK, Ruderman NB, Tomas E: Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am J Physiol Endocrinol Metab. 2006, 291: E175-81. 10.1152/ajpendo.00453.2005View ArticlePubMedGoogle Scholar
- Tsukamoto H, Hishinuma T, Suzuki N, Tayama R, Hiratsuka M, Yoshihisa T, Mizugaki M, Goto J: Thiazolidinediones increase arachidonic acid release and subsequent prostanoid production in a peroxisome proliferator-activated receptor gamma-independent manner. Prostaglandins Other Lipid Mediat. 2004, 73: 191-213. 10.1016/j.prostaglandins.2004.01.008View ArticlePubMedGoogle Scholar
- Aizawa Y, Kawabe J, Hasebe N, Takehara N, Kikuchi K: Pioglitazone enhances cytokine-induced apoptosis in vascular smooth muscle cells and reduces intimal hyperplasia. Circulation. 2001, 104: 455-460.View ArticlePubMedGoogle Scholar
- Floriano-Sanchez E, Villanueva C, Medina-Campos ON, Rocha D, Sanchez-Gonzalez DJ, Cardenas-Rodriguez N, Pedraza-Chaverri J: Nordihydroguaiaretic acid is a potent in vitro scavenger of peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid and prevents in vivo ozone-induced tyrosine nitration in lungs. Free Radic Res. 2006, 40: 523-533. 10.1080/10715760500419365View ArticlePubMedGoogle Scholar
- Mehta JL, Hu B, Chen J, Li D: Pioglitazone inhibits LOX-1 expression in human coronary artery endothelial cells by reducing intracellular superoxide radical generation. Arterioscler Thromb Vasc Biol. 2003, 23: 2203-2208. 10.1161/01.ATV.0000094411.98127.5FView ArticlePubMedGoogle Scholar
- Bond M, Chase AJ, Baker AH, Newby AC: Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc Res. 2001, 50: 556-565. 10.1016/S0008-6363(01)00220-6View ArticlePubMedGoogle Scholar
- Bondeson J, Brennan F, Foxwell B, Feldmann M: Effective adenoviral transfer of IkappaBalpha into human fibroblasts and chondrosarcoma cells reveals that the induction of matrix metalloproteinases and proinflammatory cytokines is nuclear factor-kappaB dependent. J Rheumatol. 2000, 27: 2078-2089.PubMedGoogle Scholar
- Chase AJ, Bond M, Crook MF, Newby AC: Role of nuclear factor-kappa B activation in metalloproteinase-1, -3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo. Arterioscler Thromb Vasc Biol. 2002, 22: 765-771. 10.1161/01.ATV.0000015078.09208.92View ArticlePubMedGoogle Scholar
- Schreiber E, Matthais P, Muller MM, Schaffner W: Rapid detection of octamer binding protein with ‘mini-extracts’ prepared from a small number of cells. Nuc Acids Res. 1989, 17: 6419-10.1093/nar/17.15.6419. 10.1093/nar/17.15.6419View ArticleGoogle Scholar
- Borghaei RC, Sullivan C, Mochan E: Identification of a cytokine-induced repressor of interleukin-1 stimulated expression of stromelysin 1 (MMP-3). J Biol Chem. 1999, 274: 2126-2131. 10.1074/jbc.274.4.2126PubMed CentralView ArticlePubMedGoogle Scholar