Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2009 Dec 1.
Published in final edited form as: J Endod. 2008 Oct 18;34(12):1480–1484. doi: 10.1016/j.joen.2008.09.003

The potential role of suppressors of cytokine signaling (SOCS) in the attenuation of inflammatory reaction and alveolar bone loss associated with apical periodontitis

Renato Menezes 1, Thiago Pompermaier Garlet 2, Ana Paula Fávaro Trombone 2, Carlos Eduardo Repeke 1, Ariadne Letra 1, José Mauro Granjeiro 3,4, Ana Paula Campanelli 1, Gustavo Pompermaier Garlet 1
PMCID: PMC2719713  NIHMSID: NIHMS125064  PMID: 19026878

Abstract

Inflammatory cytokines contribute to periapical tissue destruction. Their activity is potentially regulated by SOCS (suppressors of cytokine signaling), which downregulate signal transduction as part of an inhibitory feedback loop. We investigated the expression of the cytokines TNF-α, IL-10 and RANKL, and SOCS-1, -2 and -3 by Real Time-PCR in 57 periapical granulomas and 38 healthy periapical tissues. Periapical granulomas exhibited significant higher SOCS-1, -2 and -3, TNF-α, IL-10 and RANKL mRNA levels when compared to healthy controls. Significant positive correlations were found between SOCS1 and IL-10, and between SOCS3 and IL-10. Significant inverse correlations were observed between SOCS1 and TNF-α, SOCS1 and RANKL, and SOCS3 and TNF-α. Increased SOCS-1, -2 and -3 mRNA levels in periapical granulomas may be related to the downregulation of inflammatory cytokines in these lesions; therefore, SOCS molecules may have a role in the dynamics of periapical granulomas development.

Keywords: suppressors of cytokine signaling, SOCS, cytokines, TNF-alpha, RANKL, inflammation, periapical granulomas

1. INTRODUCTION

Cytokines play a major role in inflammatory and immune responses within the bone microenvironment. The balance between pro- and anti-inflammatory mediators determines the outcome of resorption in bone destructive diseases, including periapical granulomas (1). The recognition of microbial structures such as lipopolysaccharides from Gram-negative bacteria through Toll-like receptors (TLRs) triggers intracellular signaling pathways that culminate in an inflammatory cytokine response and bone lesions (2). Previous studies have demonstrated that proinflammatory cytokines such as receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor alpha (TNF-α), members of the TNF super family, are established agents in the pathogenesis of chronic inflammatory diseases including pulpitis and apical periodontitis (3–5). TNF-α is a potent immunologic mediator of acute and chronic inflammatory responses (6) and has the ability to increase bone resorption (7). On the other hand, IL-10 is a pleiotropic cytokine with strong anti-inflammatory properties, regulating B-cell proliferation and differentiation and exhibiting immunoregulatory activities (8). IL-10 directly affects osteoclast precursors and inhibits osteoclast generation and activation (9) and has been suggested as an important suppressor factor for periodontal disease (10) and apical periodontitis (11) development in mice.

Activation of cytokine signaling via the Janus kinase (JAK) and activators of transcription (STAT) pathways may represent a key mechanism by which inflammatory cytokines contribute to osteoclast formation. Members of the suppressors of cytokine signaling (SOCS) family, which comprise eight proteins (SOCS-1 to -7, and cytokine-inducible SH2-domain-containing protein-CIS), may inhibit theses pathways. The SOCS genes are activated in response to a diverse range of microbial and immunological factors (12–14). Individual SOCS are capable of inhibiting multiple cytokines, although mechanisms of binding affinity are still unclear (13, 14). SOCS-1 can be induced by cytokines that use the JAK-STAT signaling pathway, including TNF-α, IL-6, and IFN-γ, and it has been shown to inhibit the upregulation of these same inflammatory cytokines (12, 15, 16). SOCS-2 mediates the anti-inflammatory properties of aspirin-induced lipoxin in vivo (17). SOCS-3 is strongly induced by IL-1, IL-6, IL-10 and IFN-γ, and its main role appears to be the attenuation of inflammatory cytokine signaling (12, 14). Some investigators have suggested that SOCS gene expression can be induced by a range of microbial stimuli, including lipopolysaccharides and CpG oligonucleotides, and that particularly SOCS-1 is a negative regulator of the lipopolysaccharide-induced inflammatory effects via inhibition of TLR4 signaling (13, 17–19) (Figure 1). While the expression of SOCS in healthy tissues is generally absent or minimal, different degrees of upregulated SOCS expression in inflamed tissues may determine the outcome of inflammatory reaction. Therefore, we hypothesize that a differential expression of SOCS in periapical environment could interfere in the expression inflammatory cytokines such as TNF-α and RANKL, which would be relevant to periapical granulomas outcome.

Figure 1. The mechanisms of SOCS (suppressors of cytokine signaling) action in inflammatory cells and osteoclast precursors.

Figure 1

Open in a new tab

A schematic representation of mechanisms of SOCS (suppressors of cytokine signaling) action in inflammatory cells and osteoclast precursors. A) The inflammatory signaling triggered by LPS or cytokines such as TNF-α and IL-1β (1) may involve several signaling intermediates such as JAK/STAT, TRAF6 (2) and transcription factors such as NFkB (3), which initiate specific mRNA transcription (mRNAa, mRNAb) at the nucleus (4). The mRNA is translated into proteins, which will exert their biological roles after secretion (5). Inflammatory signaling also induces the expression of SOCS genes (mRNAsocs)(6), which is increased by IL-10 (7). The conversion of SOCS into non-secreted proteins (8) allows their intracellular action, which consists in the inhibition of inflammatory signaling (9), dampening therefore the inflammatory effects of LPS and cytokines. B) The interaction of RANKL with the receptor RANK (1) expressed by osteoclast precursors leads to the intracellular signaling that involves TRAF6 (2) and the transcription factor NFkB (3), which leads to osteoclast differentiation and activation, and initiate specific mRNA transcription (mRNAa, mRNAb) at the nucleus (4). Activated osteoclasts produce enzymes such as Cathepsin K and MMPs (5), involved in bone resorption. The expression of SOCS (mRNAsocs)(6), whose inducing factors in osteoclast precursors remain to be identified (7), may impair osteoclast differentiation and activation through the inhibition/degradation of TRAF6 and NFkB (8).

Therefore, in this study we investigated the expression of cytokine suppressors SOCS-1, -2 and -3 in human periapical granulomas, and their correlations with immunoregulatory cytokines, in order to improve understanding of some of the underlying mechanisms during periapical lesions development.

2. MATERIAL AND METHODS

This study was approved by the Institutional Review Board at Bauru Dental School. Fifty-seven periapical granulomas were collected from previously selected patients aged 15–58 years (average age 23.15 years, 27 females and 30 males) submitted to periapical surgery and curettage of the tissues as part of their clinical treatment. The diagnosis of periapical lesion was based on a radiographic image showing clear bone loss and disappearance of the periodontal ligament space in the periapical region. The collected lesions were divided in 2 parts for histopathological and molecular analyses. Routine histopathologic examination (hematoxylin-eosin staining of serially sectioned specimen) was performed, and granulomas represented a severe infiltration of inflammatory cells with no evidences of epithelial cells, i.e. epithelial lining and/or epithelial infiltration within the lesion. Periapical cysts were classified as fully developed cavities lined by stratified squamous epithelium and a fibrous capsule, and were excluded from the sample. Partially epithelized lesions, considered in some studies epithelized granulomas, were also excluded, and will be properly analyzed comparatively with cysts and granulomas in a further study. Lesion diameter was obtained by direct measurement using an endodontic ruler onto the periapical radiograph (taken with an intraoral film positioner).

Periodontal ligaments were used as control specimens, obtained from teeth extracted for orthodontic purposes from 38 subjects (20 males and 18 females, age 17–23 years) presenting with good oral health. Patients presenting medical history indicating use of systemic modifiers of bone metabolism, antibiotic, anti-inflammatory, hormonal or other assisted drug therapy within 6 months prior to the study, with primary or secondary acute periodontitis, or females who were pregnant or nursing were not included in the study.

Total RNA was extracted from samples using TRIZOL reagent (Life Technologies, Grand Island, NY, US), and complementary DNA (cDNA) was synthesized using 3μg of RNA through a reverse transcription reaction as previously described (20). Real Time-PCR quantitative mRNA analyses were performed in a MiniOpticon thermocycler (BioRad, Hercules, CA, US) using SYBR-green chemistry (Invitrogen, Carlsbad, CA, US), with specific primers previously described (20). Determination of the relative levels of gene expression was performed using the cycle threshold (Ct) method, in reference to beta-actin, as described elsewhere (20). PCR conditions were: 95°C (10min), 40 cycles at 94°C (1min), annealing at 56°C (1min), and 72°C (2min). Results are depicted as the mean mRNA expression from triplicate measurements normalized by internal control beta-actin. Statistical analyses included ANOVA followed by Bonferroni correction, in GraphPad Prism 4.0 (GraphPad Software Inc, San Diego, CA, US). P≤0.05 was considered statistically significant.

3. RESULTS

SOCS-1, -2 and -3, TNF-α, IL-10 and RANKL mRNA expression was significantly more frequent and intense in diseased tissues than in healthy tissues (p<0.001) (Figure 2). The levels of IL-10 showed a positive correlation with SOCS1 (r2=0.1302, p=0.0058) and SOCS3 (r2=0.1085, p=0.0124), while the levels of SOCS1 and TNF-α (r2=0.1857, p=0.0008), SOCS1 and RANKL (r2=0.0923, p=0.0116), and SOCS3 and TNF-α (r2=0.1857, p=0.0008) were negatively correlated (Figure 3). A positive correlation was also observed between TNF-α and RANKL, and a trend for negative correlation was found for IL-10 and RANKL (data not shown). SOCS1 (r2=0.0705, p=0.0359) and SOCS2 (r2=0.0892, p=0.0140) mRNA levels were inversely correlated with lesion size; however, for SOCS3 only a trend toward inverse correlation was verified (r2=0.0238, p=0.1516) (Figure 3).

Figure 2. Quantitative expression of SOCS, TNF-α, IL-10 and RANKL in periapical granulomas.

Figure 2

Open in a new tab

Total RNA was extracted from periapical granulomas (G, N=57) and periodontal ligament control samples (C, N=38), and levels of SOCS1, SOCS2, SOCS3, TNF-α, IL-10 and RANKL mRNA were measured quantitatively by RealTimePCR SYBR-Green system. The results are presented as expression of the individual mRNAs, with normalization to housekeeping gene using the Ct method. * Statistically significant difference between C and G (p<0.001).

Figure 3. Correlations between the expression of SOCS and cytokines in periapical granulomas and with the radiographic diameter of the lesions.

Figure 3

Open in a new tab

Total RNA was extracted from periapical granulomas (N=57)(A), of SOCS1, SOCS2, SOCS3, TNF-α, IL-10 and RANKL mRNA were measured quantitatively by RealTimePCR SYBR-Green system. Linear regression analysis was used to test the correlations between the levels of SOCS and cytokines expression, and also between SOCS and the radiographic diameter of the lesions. Values of p and r2 are identified in the graphs.

4. DISCUSSION

Proinflammatory cytokines play a fundamental role in periapical bone destruction through the induction of RANKL, a gene directly involved in osteoclast activation (5, 21, 22). On the other hand, the protective mechanisms against bone resorption are not fully understood. In this study, we used samples of human periapical granulomas and investigated the expression of SOCS molecules (regarded as potentially protective) and cytokines involved in RANKL induction (TNF-α) and inhibition (IL-10) in order to access their possible role in the bone resorption process associated with these endodontic lesions.

Our results showed that human periapical granulomas presented significantly higher levels of SOCS-1, -2 and -3 mRNA when compared to healthy periapical tissues, indicating a possibly active role for SOCS in the pathogenesis of periapical granulomas. SOCS proteins are negative regulators of the inflammatory signaling triggered by toll-like receptors (TLRs) and pro-inflammatory cytokines, and attenuate signal transduction as part of a negative feedback loop to inhibit the response to subsequent stimuli (12). Therefore, in accordance with our findings, SOCS are usually absent or minimal in healthy tissues, and their upregulated and differential expression in inflamed tissues may determine the outcome of inflammatory reaction (12). Both SOCS-1 and SOCS-3 negatively regulate the innate and adaptive immune mechanisms in inflammatory arthritis (23), and their deficiency results in increased tissue destruction (24, 25). SOCS-2 is a key intracellular mediator of the anti-inflammatory actions of lipoxins and its induction has been suggested to represent a general anti-inflammatory pathway responsible for controlling several innate responses (26).

Furthermore, the expression of SOCS has been shown to tune pro-inflammatory signals (like TLRs and cytokines signaling) to prevent excessive inflammatory damage to the host tissues (14, 17, 19, 27). Both LPS (which is a TLR-ligand) and several cytokines are released in root canal infection, and are involved in the development of periapical lesions (28). Therefore, we speculate that SOCS may contribute to the regulation of inflammatory molecules in the periapical microenvironment. Accordingly, our results demonstrated an inverse correlation between mRNA levels of SOCS-1 and TNF-α, SOCS-1 and RANKL, and SOCS-3 with TNF-α in periapical granulomas. TNF exacerbates bone resorption through the upregulation of RANKL expression (29). On the other hand, we found a positive correlation between SOCS1, SOCS3 and IL-10. The anti-inflammatory effects of IL-10, which involve inhibition of inflammatory mediators of mRNA transcription, may involve the participation of SOCS proteins, mainly SOCS1 and SOCS3 (30–32). Interestingly, IL-10 attenuates experimental periapical lesion progression (11), suggesting that IL-10-induced SOCS may down regulate the inflammatory signaling that leads to TNF-α mRNA transcription, which in turn could down regulate RANKL levels and interfere with lesion progression. Corroborating our findings, a similar pattern of co-expression of SOCS and cytokines was described in periodontal diseases, where increased levels of SOCS-1 and -3 were associated with non progressive gingivitis lesions (33).

SOCS-1 and -3 levels showed a trend toward negative correlation with lesion size. This could be explained in part by the association of SOCS-1 and -3 with lower RANKL expression. We have recently demonstrated that RANKL/OPG ratio is possibly associated with stable or progressive stages of periapical granulomas (34). Surprisingly, SOCS-2, not associated with RANKL expression, presented a significant negative correlation with lesion size. SOCS-2 was described to mediate the ubiquitinylation and proteasome-mediated degradation of TRAF6 (26), a RANKL-induced transcription factor essential to osteoclast development. Therefore, in addition to modulating inflammatory signaling, it is also possible that SOCS proteins influence signaling pathways involved in osteoclast differentiation and activation (27, 35).

To our knowledge, this is the first demonstration of a differential expression of SOCS-1, -2 and -3 mRNA expression in healthy and diseased human periapical tissues. These SOCS proteins were found to be differentially associated with molecules involved in the exacerbation or attenuation of bone loss, suggesting their possible involvement in the pathogenesis of the periapical lesions, as follows: 1) the expression of SOCS in inflammatory cells, induced as a negative feedback in response to inflammatory cytokines and microbial signaling and upregulated by IL-10, blocks further pro-inflammatory signaling and consequently dampens the inflammatory reaction (as exemplified in Fig. 1A); 2) the decrease in inflammatory mediators expression, such as TNF-α, resulting thereafter in a lower expression of RANKL, which in turn attenuates the bone resorption associated with periapical granulomas; and 3) SOCS also can directly on osteoclasts precursors through the inhibition of the TRAF6 and NFκB, molecules with a essential role in the differentiation and activation of osteoclasts (as exemplified in Fig. 1B). Therefore, we can consider that SOCS can attenuate periapical lesions progression at multiple steps.

Taken together, our data suggests that SOCS may potentially down regulate signaling events involved in osteoclast differentiation and activation, which consequently could interfere in lesion outcome, pointing to a promising role of SOCS as therapeutic targets to clinically interfere in bone resorption process. Indeed, experiments in a mouse model of periapical lesions, in which SOCS will be both induced and inhibited, are underway to confirm such hypothesis. Furthermore, comparative analysis of SOCS expression in different types of periapical lesions, as well the elucidation of its spatial expression within the lesions certainly will contribute to the understanding of periapical lesions pathogenesis. However, it is also important to consider that the pro- and anti-inflammatory networks implicated in the immunopathogenesis of apical periodontitis are very complex. In addition to proteins of the SOCS family, other regulatory molecules such as sMyD88, IRAK-M, Tollip and TRAILR have been suggested as important negative regulators of inflammatory signaling and could play important roles in apical periodontitis. Noteworthy is that understanding the role of regulators of cell signaling in the development of periapical diseases may provide the basis for future therapeutic interventions.

5. CONCLUSION

Our study demonstrates that SOCS-1, -2 and -3 are differentially expressed in healthy and diseased human periapical tissues, and also differentially associated with molecules involved in the exacerbation or attenuation of bone loss. Based on these findings, we suggest that SOCS may potentially downregulate signaling events involved in inflammatory reaction and osteoclast differentiation and activation, and interfere directly in the development and progression of periapical lesions. Therefore, SOCS are promising therapeutic targets to clinically interfere in periapical bone resorption process.

Abbreviations

RANK

Receptor activator of NFκB

RANKL

Receptor activator of NFκB-ligand

OPG

osteoprotegerin

SOCS

suppressors of cytokine signaling

TNF-α

tumor necrosis factor-alpha

IL-10

Interleukin-10

STAT

signal transducers and activators of transcription

TLRs

Toll-like receptors

CIS

cytokine-Inducible SH2-domain-containing protein

Footnotes

All the authors declare free of any conflict of interest.

References

  • 1.Silva TA, Garlet GP, Fukada SY, Silva JS, Cunha FQ. Chemokines in oral inflammatory diseases: apical periodontitis and periodontal disease. J Dent Res. 2007;86:309–19. doi: 10.1177/154405910708600403. [DOI] [PubMed] [Google Scholar]
  • 2.Madianos PN, Bobetsis YA, Kinane DF. Generation of inflammatory stimuli: how bacteria set up inflammatory responses in the gingiva. J Clin Periodontol. 2005;32 (suppl):57–71. doi: 10.1111/j.1600-051X.2005.00821.x. [DOI] [PubMed] [Google Scholar]
  • 3.Safavi KE, Rossomando ER. Tumor necrosis factor identified in periapical tissue exudates of teeth with apical periodontitis. J Endod. 1991;17:12–4. doi: 10.1016/S0099-2399(07)80154-3. [DOI] [PubMed] [Google Scholar]
  • 4.Danin J, Linder LE, Lundqvist G, Andersson L. Tumor necrosis factor-alpha and transforming growth factor-beta1 in chronic periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:514–7. doi: 10.1067/moe.2000.108958. [DOI] [PubMed] [Google Scholar]
  • 5.Menezes R, Bramante CM, da Silva Paiva KBS, et al. Receptor activator NFkB-ligand and osteoprotegerin protein expression in human periapical cysts and granulomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:404–9. doi: 10.1016/j.tripleo.2005.10.054. [DOI] [PubMed] [Google Scholar]
  • 6.Birkedal-Hansen H. Role of cytokines and inflammatory mediators in tissue destruction. J Periodontal Res. 1993;28:500–10. doi: 10.1111/j.1600-0765.1993.tb02113.x. [DOI] [PubMed] [Google Scholar]
  • 7.Manolagas SC. Role of cytokines in bone resorption. Bone. 1995;17:63S–67S. doi: 10.1016/8756-3282(95)00180-l. [DOI] [PubMed] [Google Scholar]
  • 8.Volk H, Asadullah K, Gallagher G, Sabat R, Grutz G. IL-10 and its homologs: important immune mediators and emerging immunotherapeutic targets. Trends Immunol. 2001;22:414–7. doi: 10.1016/s1471-4906(01)01985-8. [DOI] [PubMed] [Google Scholar]
  • 9.Mohamed SG, Sugiyama E, Shinoda K, et al. Interleukin-10 inhibitis RANKL-mediated expression of NFATcl in part via suppression of c-Fos and c-Jun in RAW264.7 cells and mouse bone marrow cells. Bone. 2007;41:592–602. doi: 10.1016/j.bone.2007.05.016. [DOI] [PubMed] [Google Scholar]
  • 10.Sasaki H, Okamatsu Y, Kawai T, Kent R, Taubman M, Stashenko P. The interleukin-10 knockout mouse is highly susceptible to Porphyromonas gingivalis-induced alveolar bone loss. J Periodontal Res. 2004;39:432–441. doi: 10.1111/j.1600-0765.2004.00760.x. [DOI] [PubMed] [Google Scholar]
  • 11.De Rossi A, Rocha LB, Rossi MA. Interferon-gamma, interleukin-10, Intercellular adhesion molecule-1, and chemokine receptor 5, but not interleukin-4, attenuate the development of periapical lesions. J Endod. 2008;34:31–8. doi: 10.1016/j.joen.2007.09.021. [DOI] [PubMed] [Google Scholar]
  • 12.Alexander WS, Hilton DJ. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol. 2004;22:503–29. doi: 10.1146/annurev.immunol.22.091003.090312. [DOI] [PubMed] [Google Scholar]
  • 13.Naka T, Fujimoto M, Tsutsui H, Yoshimura A. Negative regulation of cytokine and TLR signalings by SOCS and others. Adv Immunol. 2005;87:61–122. doi: 10.1016/S0065-2776(05)87003-8. [DOI] [PubMed] [Google Scholar]
  • 14.Rakesh K, Agrawal DK. Controlling cytokine signaling by constitutive inhibitors. Biochem Pharmacol. 2005;70:649–57. doi: 10.1016/j.bcp.2005.04.042. [DOI] [PubMed] [Google Scholar]
  • 15.Starr R, Wilson TA, Viney EM, et al. A family of cytokine-inducible inhibitors of signaling. Nature. 1997;387:917–21. doi: 10.1038/43206. [DOI] [PubMed] [Google Scholar]
  • 16.Morita Y, Naka T, Kawazoe Y, et al. Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha-induced cell death in fibroblasts. Proc Natl Acad Sci USA. 2000;97:5405–10. doi: 10.1073/pnas.090084797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Machado FS, Johndrow JE, Esper L, et al. Anti-inflammatory actions of lipoxin A (4) and aspirin-triggered lipoxin are SOCS-2 dependent. Nat Med. 2006;12:330–4. doi: 10.1038/nm1355. [DOI] [PubMed] [Google Scholar]
  • 18.Dalpke AH, Opper S, Zimmermann S, Heeg K. Supressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J Immunol. 2001;166:7082–89. doi: 10.4049/jimmunol.166.12.7082. [DOI] [PubMed] [Google Scholar]
  • 19.Nakagama R, Naka T, Tsutsui H, et al. SOCS-1 participates in negative regulation of LPS responses. Immunity. 2002;17:677–87. doi: 10.1016/s1074-7613(02)00449-1. [DOI] [PubMed] [Google Scholar]
  • 20.Garlet GP, Martins W, Jr, Fonseca BA, Ferreira BR, Silva JS. Matrix metalloproteinases, their physiological inhibitors and osteoclast factors are differentially regulated by the cytokine profile in human periodontal disease. J Clin Periodontol. 2004;31:671–79. doi: 10.1111/j.1600-051X.2004.00545.x. [DOI] [PubMed] [Google Scholar]
  • 21.Sabeti M, Simon J, Kermani V, Valles Y, Rostein I. Detection of receptor activator of NF-κB ligand in apical periodontitis. J Endod. 2005;31:17–8. doi: 10.1097/01.don.0000134210.95473.a7. [DOI] [PubMed] [Google Scholar]
  • 22.Kawashima N, Suzuki N, Yang G, et al. Kinetics of RANKL, RANK and OPG expressions in experimentally induced rat periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103:707–11. doi: 10.1016/j.tripleo.2006.11.036. [DOI] [PubMed] [Google Scholar]
  • 23.Wong PK, Egan PJ, Croker BA, et al. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest. 2006;116:1571–81. doi: 10.1172/JCI25660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Egan PJ, Lawlor KE, Alexander WS, Wicks IP. Suppressor of cytokine signaling-1 regulates acute inflammatory arthritis and T cell activation. J Clin Invest. 2003;11:915–24. doi: 10.1172/JCI16156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.de Hooge AS, van de Loo FA, Koenders MI, et al. Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice. Arthritis Rheum. 2004;50:2014–23. doi: 10.1002/art.20302. [DOI] [PubMed] [Google Scholar]
  • 26.Machado FS, Esper L, Dias A, et al. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6. J Exp Med. 2008;205:1077–86. doi: 10.1084/jem.20072416. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 27.Mansell A, Smith R, Doyle SL, et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol. 2006;7:148–155. doi: 10.1038/ni1299. [DOI] [PubMed] [Google Scholar]
  • 28.Hou L, Sasaki H, Stashenko P. Toll-like receptor 4-deficient mice have reduced bone destruction following mixed anaerobic infection. Infect Immun. 2000;68:4681–7. doi: 10.1128/iai.68.8.4681-4687.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Garlet GP, Cardoso CR, Campanelli AP, et al. The dual role of p55 tumour necrosis factor-alpha receptor in Actinobacillus actinomycetemcomitans-induced experimental periodontitis: host protection and tissue destruction. Clin Exp Immunol. 2007;147:128–38. doi: 10.1111/j.1365-2249.2006.03260.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Qin H, Roberts KL, Niyongere SA, Cong Y, Elson CO, Benveniste EN. Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. J Immunol. 2007;179:5966–76. doi: 10.4049/jimmunol.179.9.5966. [DOI] [PubMed] [Google Scholar]
  • 31.Qasimi P, Ming-Lum A, Ghanipour A, et al. Divergent mechanisms utilized by SOCS3 to mediate interleukin-10 inhibition of tumour necrosis factor alpha and nitric oxide production by macrophages. J Biol Chem. 2006;281:6316–24. doi: 10.1074/jbc.M508608200. [DOI] [PubMed] [Google Scholar]
  • 32.Berlato C, Cassatella MA, Kinjyo I, Gatto L, Yoshimura A, Bazzoni F. Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J Immunol. 2002;168:6404–11. doi: 10.4049/jimmunol.168.12.6404. [DOI] [PubMed] [Google Scholar]
  • 33.Garlet GP, Cardoso CR, Campanelli AP, et al. Expression of suppressors of cytokine signaling in diseased periodontal tissues: a stop signal for disease progression? J Periodontal Res. 2006;41:580–4. doi: 10.1111/j.1600-0765.2006.00908.x. [DOI] [PubMed] [Google Scholar]
  • 34.Menezes R, Garlet TP, Letra A, et al. Differential patterns of Receptor Activator of Nuclear Factor Kappa B Ligand/Osteoprotegerin expression in human periapical granulomas: Possible association with progressive or stable nature of the lesions. J Endod. 2008 doi: 10.1016/j.joen.2008.05.002. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Hayashi T, Kaneda T, Toyama Y, Kumegawa M, Hakeda Y. Regulation of receptor activator of NF-kappa B ligand-induced osteoclastogenesis by endogenous interferon-beta (INF-beta) and suppressors of cytokine signaling (SOCS). The possible counteracting role of SOCSs- in IFN-beta-inhibited osteoclast formation. J Biol Chem. 2002;277:27880–6. doi: 10.1074/jbc.M203836200. [DOI] [PubMed] [Google Scholar]

RESOURCES