| Sign In to gain access to subscriptions and/or personal tools. |
IL-1β and TNF-
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Regulate IL-6-type Cytokines in Gingival Fibroblasts |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Interleukin-6 (IL-6)-type cytokines are pleiotropic molecules capable of stimulating bone resorption and expressed by numerous cell types. In the present study, we tested the hypothesis that gingival fibroblasts may exert local osteotropic effects through production of IL-6 and related cytokines. IL-6-type cytokine expression and regulation by IL-1β and tumor necrosis factor-
(TNF-) were studied in fibroblasts from the non-inflamed gingiva of healthy individuals. Constitutive mRNA expression of IL-6, IL-11, and leukemia inhibitory factor (LIF), but not of oncostatin M (OSM), was demonstrated, as was concentration-dependent stimulation of IL-6 and LIF mRNA and of protein by IL-1β and TNF-. IL-11 mRNA and protein were concentration-dependently stimulated by IL-1β. The signaling pathway involved in IL-6 and LIF mRNA stimulation involved MAP kinases, but not NF-
B. The findings support the view that resident cells may influence the pathogenesis of periodontal disease through osteotropic IL-6-type cytokine production mediated by activation of MAP kinases. Abbreviations: IL-1 (interleukin-1); IL-1β (interleukin-1β); IL-6 (interleukin-6); IL-11 (interleukin-11); LIF (leukemia inhibitory factor); OSM (oncostatin M); (1)-coll. I ((1)-collagen I); ALP (alkaline phosphatase); BMP-2 (bone morphogenetic protein-2); OC (osteocalcin); BSP (bone sialoprotein); TNFR I (tumor necrosis factor receptor I); TNFR II (tumor necrosis factor receptor II); IL-1R1 (interleukin-1 receptor 1); GAPDH (glyceraldehyde-3-phosphate dehydrogenase); RPL13A (ribosomal protein L13A); mRNA (messenger ribonucleic acid); cDNA (complementary deoxyribonucleic acid); PCR (polymerase chain-reaction); BCA (bicinchoninic acid); ELISA (enzyme-linked immunosorbent assay); -MEM ( modification of Minimum Essential Medium); and FCS (fetal calf serum).
Key Words: fibroblasts • IL-6-type cytokines • periodontitis
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Periodontal disease is an inflammatory disease where host reactions to bacteria in the biofilm on tooth surfaces lead to degradation of periodontal tissues. Alveolar bone resorption in periodontitis is caused by local stimulation of osteoclasts in response to cytokines produced by infiltrating immune cells (Graves and Cochran, 2003; Lerner, 2006). It has also been shown that resident gingival cells, including epithelial cells and fibroblasts, express various cytokines (Okada and Murakami, 1998; Kusumoto et al., 2004; Belibasakis et al., 2005), and there is a possibility that osteotropic cytokines released from such cells are of additional importance in the pathogenesis of inflammation-induced bone resorption. It has been well-established that cytokines released from mononuclear leukocytes can affect the phenotype of resident fibroblasts (Murakami et al., 1999). It is possible, therefore, that release of osteotropic cytokines from inflamed gingiva is a result of the concerted actions of inflammatory leukocytes and resident cells, similar to the view that resident synovial fibroblasts may play central roles in tissue remodelling in rheumatoid arthritis (Ritchlin, 2000).
IL-6-type cytokines—including interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OSM)—are known to be stimulators of osteoclastogenesis and bone resorption in vitro (Martin et al., 1998; Ahlen et al., 2002; Palmqvist et al., 2002). Interestingly, IL-6 has been ascribed regulatory functions in periodontitis (Okada and Murakami, 1998), and IL-6 expression in human gingival fibroblasts has been reported (Kent et al., 1998; Modéer et al., 1998; Belibasakis et al., 2005). Elevated IL-6 mRNA expression was demonstrated in fibroblasts from inflamed gingival tissue, compared with expression in cells from healthy gingiva (Kent et al., 1999; Wang et al., 2003). Several studies have also demonstrated elevated IL-6 levels in gingival crevicular fluid of pathological gingival pockets compared with control samples (Mogi et al., 1999; Graves and Cochran, 2003; Lin et al., 2005). In one study, IL-11 mRNA and protein expression in gingival fibroblasts of healthy individuals was reported (Yashiro et al., 2006). However, no studies have shown LIF or OSM expression in human gingival fibroblasts, although elevated levels of LIF and OSM have been detected in gingival crevicular fluid at diseased sites in persons with periodontitis (Lin et al., 2005; Sakai et al., 2006).
The aim of the present study was to determine if gingival fibroblasts express IL-6-type cytokines, and if the expression of these cytokines is regulated by pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor- (TNF-), and if the regulatory mechanism involves MAPK kinases and NF-B.
|
MATERIALS & METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Fibroblast Cultures
Gingival fibroblasts were isolated as previously described (Lerner and Hanstrom, 1987) from gingival papillary explants obtained from nine clinically and systemically healthy voluntary donors, whose rights were protected by the Ethical Committee for Human Research, and who provided informed consent.
Gingival explants were placed at the bottom of Petri dishes with -MEM ( modification of Minimum Essential Medium) supplemented with 10% fetal calf serum (FCS), L-glutamine (Invitrogen, Paisley, UK), and antibiotics (basic medium) and left untouched for 7–10 days until outgrowth of fibroblasts from the explants was observed. The fibroblasts were then detached and seeded at a density of 3.5 x 104 cells/cm2 and cultured until cells were 80–90% confluent. Media were changed, and cells were incubated in the absence (controls) or presence of test substances for 24 hrs (mRNA), 30–60 min (Western blots), or 48 hrs (ELISA). Cells used in the experiments demonstrated a fibroblastic morphology, and cells from passages 4–7 were used in the experiments. For Western blots, cells underwent lysis, and protein concentrations were analyzed as previously described (Brechter and Lerner, 2007). For ELISA analyses, culture media were collected, and cells were washed thoroughly in serum-free medium followed by lysis in 0.2% Triton X-100. For mRNA analyses, cells underwent lysis in TRIzol LS Reagent (Applied Biosystems, Warrington, UK) or the lysis buffer supplied with the RNAqueous 4-PCR kit (Ambion Inc., Austin, TX , USA).
Gene Expression Analyses
RNA was extracted, and mRNA expression was analyzed by either semi-quantitative RT-PCR or quantitative real-time PCR (q-PCR), as previously described (Palmqvist et al., 2006). The sequences and concentrations of primers and probes, GenBank accession numbers, and numbers for the 5' and 3' ends of the nucleotides for the predicted PCR products are listed in the APPENDIX Table.
Analyses of IL-6, IL-11, LIF, and IB Protein
We assessed the protein synthesis of IL-6, IL-11, and LIF by measuring the levels of IL-6 in cell lysates and of IL-11 and LIF in culture media using commercially available ELISA kits (R&D Systems, Abingdon, UK). Cytokine concentration was normalized to total amount of cell protein, analyzed by the BCA method (Pierce, Rockford, IL, USA). Activation of the transcription factor nuclear factor-B (NF-B) in the fibroblasts by IL-1β and TNF- was assessed by Western blot analysis of inhibitor of B (IB) protein with the use of antibodies (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) and a SuperSignal chemiluminescence detection kit (Pierce Biotechnology, Rockford, IL, USA).
Bone Nodule Formation
We analyzed bone formation in fibroblast cultures by culturing gingival fibroblasts for up to 27 days in the presence of ascorbic acid and β-glycerophosphate, followed by subsequent von Kossa staining to detect phosphate deposits in mineralized nodules, a technique frequently used to assess bone nodule formation in bone cell cultures.
Statistical Analysis
Statistical analysis was performed by the non-parametric Kruskal-Wallis and Mann-Whitney tests. Results are expressed as means ± standard error of means (SEM).
SEM is shown when the height of the error bar is larger than the radius of the symbol.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Phenotypic Characterization and Constitutional Expression of Osteotropic Cytokines in Gingival Fibroblasts
Fibroblasts isolated from nine individuals were cultured in basic medium for 24 hrs. Semi-quantitative RT-PCR analyses showed that 9/9 isolates expressed
(1)-collagen I [(1)-coll.I], alkaline phosphatase (ALP), and bone morphogenetic protein-2 (BMP-2) mRNA, whereas no expression of osteocalcin (OC) or bone sialo-protein (BSP) mRNA was noted (Fig. 1A
). At variance, these genes were all expressed in primary osteoblastic cells isolated from human trabecular bone (data not shown). These results, as well as the fibroblastic morphology of the cells, indicate that the cells used expressed a fibroblastic, rather than a periodontal ligament cell or osteoblastic, phenotype. In addition, no von Kossa-positive mineralized bone nodules were observed in long-term cultures (27 days) of the gingival fibroblasts (data not shown).
|
RT-PCR analyses demonstrated constitutive expression in 7/7 fibroblast isolates of IL-6, IL-11, and LIF (Fig. 1B
). In contrast, OSM mRNA was not expressed (Fig. 1B), although it could be detected in human peripheral mononuclear leukocytes (data not shown). Additionally, expression of TNFR I, TNFR II, and IL-1R1 mRNA was observed in all 7 cell cultures (Fig. 1B). IL-1β mRNA was clearly expressed in 2/7 cell cultures and weakly in 3/7, whereas TNF- mRNA could not be detected in any unstimulated cell cultures.
Regulation of Osteotropic Cytokine mRNA Expression by IL-1β and TNF- in Gingival Fibroblasts
Gingival fibroblasts isolated from five individuals were cultured with or without IL-1β (100 pg/mL; R&D Systems, Abingdon, UK) or TNF- (50 ng/mL; R&D Systems, Abingdon, UK) for 24 hrs. Increased mRNA expression of IL-6 and LIF in 5/5 isolates treated with IL-1β and TNF- was demonstrated by semi-quantitative RT-PCR (Fig. 2). Similarly, increased IL-11 mRNA was noted in 5/5 isolates treated with IL-1β, while an increase was noted in 1/5 cells treated with TNF-. In contrast, OSM mRNA was not detected in IL-1β- or TNF--stimulated cells, although the PCRs were run for a higher number of cycles compared with the PCRs for IL-6, IL-11, and LIF. Furthermore, the expression of TNF- was enhanced by TNF- in 5/5 isolates, and by IL-1β in 4/5 cell isolates, although this could be demonstrated only at higher cycle numbers. IL-1β mRNA was increased by IL-1β and TNF- in all 5 isolates (Fig. 2).
|
Concentration-dependent Regulation of mRNA and Protein for IL-6-type Cytokines by IL-1β and TNF-
in Gingival FibroblastsGingival fibroblasts were cultured in the absence or presence of IL-1β (10–300 pg/mL) or TNF-
(0.3–30 ng/mL) for 24 (mRNA analysis) or 48 hrs (protein analysis). q-PCR demonstrated that IL-1β and TNF- concentration-dependently stimulated the mRNA expressions of IL-6 (Figs. 3A, 3B) and LIF (Figs. 3C, 3D). IL-1β concentration-dependently stimulated IL-11 mRNA (Fig. 3E).
|
ELISA analyses showed that protein expressions of IL-6 (Figs. 3F, 3G
) and LIF (Figs. 3H, 3I) were concentration-dependently stimulated by IL-1β and TNF-. IL-11 protein levels were concentration-dependently increased by IL-1β (Fig. 3J). In agreement with the RT-PCR analysis shown in Fig. 2, TNF- only marginally enhanced IL-11 protein (data not shown).
Importance of NF-B and MAPK Kinases for the Stimulatory Effects by IL-1β and TNF- on IL-6 and LIF mRNA
The NF-B inhibitor PDTC (Merck, Darmstadt, Germany) did not affect IL-1β- or TNF--induced enhanced mRNA expression of IL-6 or LIF (Figs. 4A-4D). Activation of NF-B involves initial IKK-dependent phosphorylation of IB, which then is released from the NF-B/IB complex and subsequently directed for proteasomal degradation. Both IL-1β and TNF- induced disappearance of IBβ protein, as an assessment of the NF-B pathway being stimulated (Fig. 4E). The p38 MAP kinase inhibitor SB203580 and the JNK MAP kinase inhibitor SP600125 (all MAP kinase inhibitors from Merck) significantly inhibited IL-1β- and TNF--induced mRNA expression of IL-6 and LIF (Figs. 4A-4D). At variance, the ERK 
MAP kinase inhibitor PD98059 did not affect IL-1β-induced IL-6 mRNA expression, but significantly decreased IL-1β-induced LIF mRNA, as well as the TNF--induced mRNA expression of both IL-6 and LIF (Figs. 4A-4D).
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The present study provides evidence that resident gingival fibroblasts express several osteotropic IL-6-type cytokines, expression of which is further enhanced by IL-1β and TNF-
. In agreement with the biological responses to IL-1β and TNF-β, we could detect mRNA for the signal-transducing IL-1 type 1 receptor and for both TNF receptor subtypes. Activation of the TNF receptors resulted in homologous increase of not only TNF-, but also of IL-1β mRNA, and activation of IL-1 receptors increased IL-1β and TNF- mRNA.
Our observations—that IL-1β and TNF- enhanced IL-6 mRNA and protein—are in accord with reports from previous investigations demonstrating increased IL-6 expression in human gingival fibroblasts stimulated by IL-1β and TNF- (Kent et al., 1998; Modéer et al., 1998).
Very few studies have assessed the expression of IL-11 in gingival fibroblasts. However, IL-11 mRNA and protein expression have previously been demonstrated in gingival fibroblasts of healthy individuals (Yashiro et al., 2006), and IL-11 protein has been detected in gingival tissue (Johnson et al., 2004). We have confirmed these observations and, in addition, have shown that IL-11 mRNA and protein expression in human gingival fibroblasts are enhanced by IL-1β, but not by TNF-. The fact that IL-1β and TNF- both enhance IL-6, and that IL-1β, but not TNF-, regulates IL-11, indicates that IL-1β and TNF- control the expression of IL-6-type cytokines by different molecular mechanisms.
LIF has been detected in GCFs in diseased periodontal pockets of persons with periodontitis (Lin et al., 2005; Sakai et al., 2006), but the source of the cytokine is unknown. Analysis of the data presented in this study shows, for the first time, that LIF was expressed in gingival fibroblasts isolated from seven different individuals, and that the expression was enhanced by both IL-1β and TNF-, with IL-1β being more potent—observations suggesting that gingival fibroblasts may be one source of LIF detected in GCFs. Similar to the present observations, LIF expression has been observed in human synovial fibroblasts stimulated by IL-1β and TNF- in vitro (Hamilton et al., 1993; Okamoto et al., 1997).
It is not known if OSM is expressed in human gingival fibroblasts. We could not detect OSM mRNA in the human gingival fibroblasts used in the present study, in neither the absence nor the presence of IL-1β or TNF-. In agreement with these observations, fibroblast cell lines derived from human synovium of persons with rheumatoid arthritis stimulated with IL-1β or TNF- demonstrated no expression of OSM, whereas IL-6, IL-11, and LIF were all expressed (Okamoto et al., 1997).
Analysis of the data presented in this paper shows that pro-inflammatory cytokines such as IL-1β and TNF- can regulate the expression of IL-6, IL-11, and LIF in gingival fibroblasts. The observation that all cytokines were regulated at both the mRNA and protein levels indicates that IL-1β and TNF- exert their effects at the level of gene transcription. It is not known, however, if the increased steady-state levels of IL-6, IL-11, and LIF mRNA resulted primarily from effects of IL-1β and TNF- on mRNA stability or on transcriptional rate. Using a pharmacological inhibitor, we obtained evidence suggesting that the mechanism by which IL-1β and TNF- stimulated IL-6 and LIF mRNA seems not to involve activation of NF-B, although both cytokines were found to activate this signal-transducing pathway. However, the MAP kinase pathway seemed to be more important, since 3 different MAP kinase inhibitors decreased the effects of the 2 cytokines, well in line with the fact that the IL-6 promoter contains AP-1-responsive elements important for the transcription of IL-6 (Xiao et al., 2004).
The abundance of fibroblasts in gingival tissue makes their secretory potential a matter of interest (Lekic et al., 1997; Takashiba et al., 2003), which led us to speculate that cytokines released from such fibroblasts may affect alveolar bone cells in persons with periodontal disease. Similarly, the fact that synovial fibroblasts can secrete a variety of cytokines and enzymes involved in the remodeling of bone and cartilage has led to the view that these cells may be important in tissue remodeling in rheumatoid arthritis (Ritchlin, 2000). In support of our speculation, the present study showed that resident gingival fibroblasts can secrete several osteotropic IL-6-type cytokines, including IL-6, IL-11, and LIF. Although the stimulatory effects of these cytokines on osteoclast formation and bone resorption in vitro have been well-documented (Martin et al., 1998; Palmqvist et al., 2002), their roles in inflammation-induced bone resorption in vivo are less well-established. However, anti-cytokine therapies targeting IL-6 have been proposed to be useful in the treatment of inflammatory osteolytic conditions (Ancey et al., 2003), and blocking of IL-6 signaling has been shown to prevent tissue erosion in animal models of arthritis (Gabay, 2006). Interestingly, a randomized clinical trial of an IL-6 receptor antagonist has been successful in decreasing tissue destruction in rheumatoid arthritis (Maini et al., 2006).
In conclusion, we here confirm that the expression of IL-6 in gingival fibroblasts can be enhanced by IL-1β and TNF- and show, for the first time, that 2 other cytokines in the IL-6 family of cytokines, IL-11 and LIF, but not OSM, can also be expressed and positively regulated by IL-1β and TNF-, by a mechanism involving MAP kinases, but not NF-B. The present study provides evidence supporting the view that gingival fibroblasts may be potential modulators of bone metabolism in periodontal disease through the secretion of IL-6-type cytokines, although this speculation needs to be substantiated by in vivo observations.
|
ACKNOWLEDGMENTS |
|---|
This work was supported by grants from the Swedish Dental Society, the Swedish Science Council, the Royal 80 Year Fund of King Gustav V, the Swedish Rheumatism Association, and the County Council of Västerbotten.
Dr. Östen Ljunggren, Department of Medicine, University of Uppsala, Sweden, and Dr. Peyman Kelk, Department of Periodontology, Umeå University, Sweden, are acknowledged for kind provisions of primary human osteoblast and leukocyte cDNA, respectively.
|
FOOTNOTES |
|---|
A supplemental appendix to this article is published electronically only at http://jdr.iadrjournals.org/cgi/content/full/87/6/558/DC1.
Received for publication November 16, 2006. Revision received January 24, 2008. Accepted for publication January 30, 2008.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
|---|
- Ahlen J, Andersson S, Mukohyama H, Roth C, Backman A, Conaway HH, et al. (2002). Characterization of the bone-resorptive effect of interleukin-11 in cultured mouse calvarial bones. Bone 31:242–251.
- Ancey C, Kuster A, Haan S, Herrmann A, Heinrich PC, Muller-Newen G (2003). A fusion protein of the gp130 and interleukin-6Ralpha ligand-binding domains acts as a potent interleukin-6 inhibitor. J Biol Chem 278:16968–16972.
[Abstract/Free Full Text] - Belibasakis GN, Johansson A, Wang Y, Chen C, Lagergard T, Kalfas S, et al. (2005). Cytokine responses of human gingival fibroblasts to Actinobacillus actinomycetemcomitans cytolethal distending toxin. Cytokine 30:56–63.[Medline] [Order article via Infotrieve]
- Brechter AB, Lerner UH (2007). Bradykinin potentiates cytokine-induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression. Arthritis Rheum 56:910–923.[CrossRef][Medline] [Order article via Infotrieve]
- Gabay C (2006). Interleukin-6 and chronic inflammation. Arthritis Res Ther 8(Suppl 2):3.
- Graves DT, Cochran D (2003). The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J Periodontol 74:391–401.[CrossRef][Medline] [Order article via Infotrieve]
- Hamilton JA, Waring PM, Filonzi EL (1993). Induction of leukemia inhibitory factor in human synovial fibroblasts by IL-1 and tumor necrosis factor-alpha. J Immunol 150:1496–1502.[Abstract]
- Johnson RB, Wood N, Serio FG (2004). Interleukin-11 and IL-17 and the pathogenesis of periodontal disease. J Periodontol 75:37–43.[CrossRef][Medline] [Order article via Infotrieve]
- Kent LW, Rahemtulla F, Hockett RD Jr, Gilleland RC, Michalek SM (1998). Effect of lipopolysaccharide and inflammatory cytokines on interleukin-6 production by healthy human gingival fibroblasts. Infect Immun 66:608–614.
[Abstract/Free Full Text] - Kent LW, Rahemtulla F, Michalek SM (1999). Interleukin (IL)-1 and Porphyromonas gingivalis lipopolysaccharide stimulation of IL-6 production by fibroblasts derived from healthy or periodontally diseased human gingival tissue. J Periodontol 70:274–282.[CrossRef][Medline] [Order article via Infotrieve]
- Kusumoto Y, Hirano H, Saitoh K, Yamada S, Takedachi M, Nozaki T, et al. (2004). Human gingival epithelial cells produce chemotactic factors interleukin-8 and monocyte chemoattractant protein-1 after stimulation with Porphyromonas gingivalis via Toll-like receptor 2. J Periodontol 75:370–379.[CrossRef][Medline] [Order article via Infotrieve]
- Lekic PC, Pender N, McCulloch CA (1997). Is fibroblast heterogeneity relevant to the health, diseases, and treatments of periodontal tissues? Crit Rev Oral Biol Med 8:253–268.
[Abstract/Free Full Text] - Lerner UH (2006). Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis. J Dent Res 85:596–607.
[Abstract/Free Full Text] - Lerner U, Hanstrom L (1987). Human gingival fibroblasts secrete non-dialyzable, prostanoid-independent products which stimulate bone resorption in vitro. J Periodontal Res 22:284–289.[Medline] [Order article via Infotrieve]
- Lin SJ, Chen YL, Kuo MY, Li CL, Lu HK (2005). Measurement of gp130 cytokines oncostatin M and IL-6 in gingival crevicular fluid of patients with chronic periodontitis. Cytokine 30:160–167.[CrossRef][Medline] [Order article via Infotrieve]
- Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al. (2006). Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 54:2817–2829.[CrossRef][Medline] [Order article via Infotrieve]
- Martin TJ, Romas E, Gillespie MT (1998). Interleukins in the control of osteoclast differentiation. Crit Rev Eukaryot Gene Expr 8:107–123.[Medline] [Order article via Infotrieve]
- Modéer T, Anduren I, Yucel-Lindberg T (1998). Bradykinin synergistically stimulates interleukin 6 production in human gingival fibroblasts challenged with interleukin 1 or tumour necrosis factor alpha. Cytokine 10:26–31.[Medline] [Order article via Infotrieve]
- Mogi M, Otogoto J, Ota N, Inagaki H, Minami M, Kojima K (1999). Interleukin 1 beta, interleukin 6, beta 2-microglobulin, and transforming growth factor-alpha in gingival crevicular fluid from human periodontal disease. Arch Oral Biol 44:535–539.[CrossRef][Medline] [Order article via Infotrieve]
- Murakami S, Hino E, Shimabukuro Y, Nozaki T, Kusumoto Y, Saho T, et al. (1999). Direct interaction between gingival fibroblasts and lymphoid cells induces inflammatory cytokine mRNA expression in gingival fibroblasts. J Dent Res 78:69–76.
[Abstract/Free Full Text] - Okada H, Murakami S (1998). Cytokine expression in periodontal health and disease. Crit Rev Oral Biol Med 9:248–266.
[Abstract/Free Full Text] - Okamoto H, Yamamura M, Morita Y, Harada S, Makino H, Ota Z (1997). The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum 40:1096–1105.[Medline] [Order article via Infotrieve]
- Palmqvist P, Persson E, Conaway HH, Lerner UH (2002). IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169:3353–3362.
[Abstract/Free Full Text] - Palmqvist P, Lundberg P, Persson E, Johansson A, Lundgren I, Lie A, et al. (2006). Inhibition of hormone and cytokine-stimulated osteoclastogenesis and bone resorption by interleukin-4 and interleukin-13 is associated with increased osteoprotegerin and decreased RANKL and RANK in a STAT6-dependent pathway. J Biol Chem 281:2414–2429.
[Abstract/Free Full Text] - Ritchlin C (2000). Fibroblast biology. Effector signals released by the synovial fibroblast in arthritis. Arthritis Res 2:356–360.[CrossRef][Medline] [Order article via Infotrieve]
- Sakai A, Ohshima M, Sugano N, Otsuka K, Ito K (2006). Profiling the cytokines in gingival crevicular fluid using a cytokine antibody array. J Periodontol 77:856–864.[CrossRef][Medline] [Order article via Infotrieve]
- Takashiba S, Naruishi K, Murayama Y (2003). Perspective of cytokine regulation for periodontal treatment: fibroblast biology. J Periodontol 74:103–110.[CrossRef][Medline] [Order article via Infotrieve]
- Wang PL, Ohura K, Fujii T, Oido-Mori M, Kowashi Y, Kikuchi M, et al. (2003). DNA microarray analysis of human gingival fibroblasts from healthy and inflammatory gingival tissues. Biochem Biophys Res Commun 305:970–973.[CrossRef][Medline] [Order article via Infotrieve]
- Xiao W, Hodge DR, Wang L, Yang X, Zhang X, Farrar WL (2004). NF-kappaB activates IL-6 expression through cooperation with c-Jun and IL6-AP1 site, but is independent of its IL6-NFkappaB regulatory site in autocrine human multiple myeloma cells. Cancer Biol Ther 3:1007–1017.[Medline] [Order article via Infotrieve]
- Yashiro R, Nagasawa T, Kiji M, Hormdee D, Kobayashi H, Koshy G, et al. (2006). Transforming growth factor-beta stimulates interleukin-11 production by human periodontal ligament and gingival fibroblasts. J Clin Periodontol 33:165–171.[Medline] [Order article via Infotrieve]
Journal of Dental Research, Vol. 87, No. 6,
558-563 (2008)
DOI: 10.1177/154405910808700614
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Chen, M. Chiba, S. Mori, M. Fukumoto, and T. Kodama Periodontal Gene Transfer by Ultrasound and Nano/Microbubbles Journal of Dental Research, November 1, 2009; 88(11): 1008 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T.-H. Huang, D. J. Taxman, E. A. Holley-Guthrie, C. B. Moore, S. B. Willingham, V. Madden, R. K. Parsons, G. L. Featherstone, R. R. Arnold, B. P. O'Connor, et al. Critical Role of Apoptotic Speck Protein Containing a Caspase Recruitment Domain (ASC) and NLRP3 in Causing Necrosis and ASC Speck Formation Induced by Porphyromonas gingivalis in Human Cells J. Immunol., February 15, 2009; 182(4): 2395 - 2404. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
