Expression of suppressors of cytokine signaling in diseased periodontal tissues: a stop signal for disease progression?

BACKGROUND AND OBJECTIVE Inflammatory cytokines are thought to trigger periodontal tissue destruction. In addition to being regulated by anti-inflammatory mediators, their activity is under the control of suppressors of cytokine signaling (SOCS), which down-regulate the signal transduction as part of an inhibitory feedback loop. We therefore investigated the expression of SOCS-1, -2 and -3, and the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-10, in different forms of human periodontal diseases. MATERIAL AND METHODS Quantitative polymerase chain reaction (RealTime-PCR) was performed with mRNA from gingival biopsies of control subjects and from that of patients with chronic gingivitis and chronic periodontitis. RESULTS Our results show that patients with chronic gingivitis and chronic periodontitis exhibit significantly higher SOCS-1, -2 and -3, TNF-alpha and interleukin-10 mRNA expression when compared with healthy controls. The data also demonstrate that SOCS-1 and -3 mRNA expression was higher in tissue from patients with chronic gingivitis than chronic periodontitis, while the levels of SOCS-2, TNF-alpha and interleukin-10 mRNA were similar in these groups. CONCLUSION The increased expression of SOCS-1, -2 and -3 mRNA in diseased periodontal tissues is believed to be involved in the down-regulation of inflammatory cytokine and Toll-like receptor signaling, and therefore in the attenuation of both the inflammatory reaction and disease severity. Furthermore, it is possible that variation in the levels of SOCS mRNA expressed in different forms of periodontal diseases may determine the stable or progressive nature of the lesions.

[1]  G. Garlet,et al.  Patterns of chemokines and chemokine receptors expression in different forms of human periodontal disease. , 2003, Journal of periodontal research.

[2]  G. Garlet,et al.  Matrix metalloproteinases, their physiological inhibitors and osteoclast factors are differentially regulated by the cytokine profile in human periodontal disease. , 2004, Journal of clinical periodontology.

[3]  A. Kantarcı,et al.  Host-mediated resolution of inflammation in periodontal diseases. , 2006, Periodontology 2000.

[4]  A. Yoshimura,et al.  Negative regulation of cytokine and TLR signalings by SOCS and others. , 2005, Advances in immunology.

[5]  M. Makuuchi,et al.  Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression. , 2005, Journal of hepatology.

[6]  W. B. van den Berg,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. , 2004, Arthritis and rheumatism.

[7]  S. Akira,et al.  Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK-STAT. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[8]  I. Cohen,et al.  Heat Shock Protein 60 Activates Cytokine-Associated Negative Regulator Suppressor of Cytokine Signaling 3 in T Cells: Effects on Signaling, Chemotaxis, and Inflammation1 , 2005, The Journal of Immunology.

[9]  L. Flowers,et al.  Treatment of Mice with the Suppressor of Cytokine Signaling-1 Mimetic Peptide, Tyrosine Kinase Inhibitor Peptide, Prevents Development of the Acute Form of Experimental Allergic Encephalomyelitis and Induces Stable Remission in the Chronic Relapsing/Remitting Form1 , 2005, The Journal of Immunology.

[10]  D. Curiel,et al.  Suppressor of cytokine signaling-1 expression by infectivity-enhanced adenoviral vector inhibits IL-6-dependent proliferation of multiple myeloma cells , 2006, Cancer Gene Therapy.

[11]  K. Heeg,et al.  Suppressors of Cytokine Signaling (SOCS)-1 and SOCS-3 Are Induced by CpG-DNA and Modulate Cytokine Responses in APCs1 , 2001, The Journal of Immunology.

[12]  Takafumi Yoshida,et al.  Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. , 2001, The Journal of clinical investigation.

[13]  K. Heeg,et al.  Suppressor of Cytokine Signaling (SOCS) Proteins Indirectly Regulate Toll-like Receptor Signaling in Innate Immune Cells*♦ , 2004, Journal of Biological Chemistry.

[14]  N. Takahashi,et al.  Regulatory mechanisms of osteoblast and osteoclast differentiation. , 2002, Oral diseases.

[15]  D. Hebenstreit,et al.  SOCS-1 and SOCS-3 inhibit IL-4 and IL-13 induced activation of Eotaxin-3/CCL26 gene expression in HEK293 cells. , 2005, Molecular immunology.

[16]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[17]  A. Yoshimura,et al.  Involvement of Suppressor of Cytokine Signaling-3 as a Mediator of the Inhibitory Effects of IL-10 on Lipopolysaccharide-Induced Macrophage Activation1 , 2002, The Journal of Immunology.

[18]  Paul J Hertzog,et al.  SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine , 1999, Cell.

[19]  Zhimin Feng,et al.  Role of bacteria in health and disease of periodontal tissues. , 2006, Periodontology 2000.

[20]  K. Rakesh,et al.  Controlling cytokine signaling by constitutive inhibitors. , 2005, Biochemical pharmacology.

[21]  J. Johndrow,et al.  Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent , 2006, Nature Medicine.

[22]  D. Kinane,et al.  Generation of inflammatory stimuli: how bacteria set up inflammatory responses in the gingiva. , 2005, Journal of clinical periodontology.

[23]  Kenji Nakanishi,et al.  SOCS-1 participates in negative regulation of LPS responses. , 2002, Immunity.

[24]  S. Nagata,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. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  W. Alexander,et al.  Suppressor of cytokine signaling-1 regulates acute inflammatory arthritis and T cell activation. , 2003, The Journal of clinical investigation.

[26]  W. Alexander,et al.  The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. , 2004, Annual review of immunology.

[27]  D. Häussinger,et al.  The MKK6/p38 Mitogen-Activated Protein Kinase Pathway Is Capable of Inducing SOCS3 Gene Expression and Inhibits IL-6-Induced Transcription , 2001, Biological chemistry.

[28]  A. Yoshimura,et al.  Divergent Mechanisms Utilized by SOCS3 to Mediate Interleukin-10 Inhibition of Tumor Necrosis Factor α and Nitric Oxide Production by Macrophages* , 2006, Journal of Biological Chemistry.

[29]  D. Kinane,et al.  Advances in the pathogenesis of periodontitis. Group B consensus report of the fifth European Workshop in Periodontology. , 2005, Journal of clinical periodontology.

[30]  Paul J Hertzog,et al.  Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation , 2006, Nature Immunology.

[31]  R. Kent,et al.  The interleukin-10 knockout mouse is highly susceptible to Porphyromonas gingivalis-induced alveolar bone loss. , 2004, Journal of periodontal research.

[32]  K. Eguchi,et al.  Increased mRNA expression of Th1-cytokine signaling molecules in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. , 2004, The Tohoku journal of experimental medicine.

[33]  T. Berglundh,et al.  Aspects of adaptive host response in periodontitis. , 2005, Journal of clinical periodontology.

[34]  A. Kantarcı,et al.  Lipoxin signaling in neutrophils and their role in periodontal disease. , 2005, Prostaglandins, leukotrienes, and essential fatty acids.

[35]  D. Graves,et al.  The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. , 2003, Journal of periodontology.

[36]  D. Kinane,et al.  Immune processes in periodontal disease: a review. , 2002, Annals of periodontology.