Periodontal diseases (PD) are chronic infectious inflammatory diseases characterized by the destruction of tooth-supporting structures, being the presence of periodontopathogens required, but not sufficient, for disease development. As a general rule, host inflammatory mediators have been associated with tissue destruction, while anti-inflammatory mediators counteract and attenuate disease progression. With the discovery of several T-cell subsets bearing distinct immunoregulatory properties, this pro- vs. anti-inflammatory scenario became more complex, and a series of studies has hypothesized protective or destructive roles for Th1, Th2, Th17, and Treg subpopulations of polarized lymphocytes. Interestingly, the “protective vs. destructive” archetype is usually considered in a framework related to tissue destruction and disease progression. However, it is important to remember that periodontal diseases are infectious inflammatory conditions, and recent studies have demonstrated that cytokines (TNF-α and IF...

Destructive and Protective Roles of Cytokines in Periodontitis: A Re-appraisal from Host Defense and Tissue Destruction Viewpoints

Transforming growth factor-beta (TGF-β) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-β are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-β is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-β. Loss of autocrine TGF-β activity and/or responsiveness to exogenous TGF-β appears to provide some epithelial cells with a growth advantage leading to malignant progression. This suggests a pro-oncogenic role for TGF-β in addition to its tumor suppressor role. During the early phase of epithelial tumorigenesis, TGF-β inhibits primary tumor development and growth by inducing cell cycle arrest and apoptosis. In late stages of tumor progression when tumor cells become resistant to growth inhibition by TGF-β due to inactivation of the TGF-β signaling pathway or aberrant regulation of the cell cycle, the role of TGF-β becomes one of tumor promotion. Resistance to TGF-β-mediated inhibition of proliferation is frequently observed in multiple human cancers, as are various alterations in the complex TGF-β signaling and cell cycle pathways. TGF-β can exert effects on tumor and stromal cells as well as alter the responsiveness of tumor cells to TGF-β to stimulate invasion, angiogenesis, and metastasis, and to inhibit immune surveillance. Because of the dual role of TGF-β as a tumor suppressor and pro-oncogenic factor, members of the TGF-β signaling pathway are being considered as predictive biomarkers for progressive tumorigenesis, as well as molecular targets for prevention and treatment of cancer and metastasis.

Transforming growth factor-β in cancer and metastasis

In contrast to the commonly accepted hypothesis of host-centred pathology, it is possible that surface bacteria, not host dysfunction, cause the chronicity and perpetual inflammation associated with chronic non-healing wounds.

Biofilms and chronic wound inflammation.

Protection against pathogens is a prerequisite for survival of most organisms. To cope with this continuous challenge, complex defense mechanisms have evolved. The construction, adaptation, and maintenance of these mechanisms are under control of an extensive network of regulatory proteins called cytokines. A great number of cytokines have been described over the last 2 decades. This review consists of an overview of cytokines that are involved in immune responses and describes some historical and general aspects as well as prospective clinical applications. Major biological effects together with information on cytokine receptors, producers, inducers, and biochemical and molecular characteristics are listed in tables. In addition, some basic information is given on cytokine receptor signal transduction. Finally, the recent discoveries of cytokine receptors functioning as coreceptors in the pathogenesis of human immunodeficiency virus are summarized.

A primer on cytokines: sources, receptors, effects, and inducers.

The immunopathogenesis of dengue haemorrhagic fever and dengue shock syndrome is thought to be mediated by a variety of host factors. Enhancing antibodies are one of the key regulating molecules. These antibodies, via antibody-dependent enhancement (ADE) of infection, are able to facilitate dengue virus (DENV) growth in Fc-bearing host cells. The mechanism of ADE-enhanced DENV production is believed to be mediated through increasing the infected-cell mass. In the present work, the effect of ADE infection was explored further, focusing on the post-entry events of ADE infection. It was hypothesized that the higher virus production in ADE infection compared with DENV infection may be due to the ability of this infection pathway to suppress key antiviral molecules. Therefore, the influence of ADE infection on pro- and anti-inflammatory cytokines, including interleukin-12 (IL-12), gamma interferon (IFN-γ), tumour necrosis factor alpha (TNF-α), IL-6 and IL-10, was investigated and it was found that DENV infection via the Fc receptor-mediated pathway was able to suppress the transcription and translation of IL-12, IFN-γ and TNF-α. In contrast, infection via this route facilitated expression and synthesis of the anti-inflammatory cytokines IL-6 and IL-10. Moreover, this study demonstrates that the ADE infection pathway also suppresses an innate anti-DENV mediator, nitric oxide radicals, by disrupting the transcription of the iNOS gene transcription factor, IRF-1, and blocking the activation of STAT-1. In conclusion, ADE infection not only facilitates the entry process, but also modifies innate and adaptive intracellular antiviral mechanisms, resulting in unrestricted DENV replication in THP-1 cells.

Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells

The aim of this study was to determine whether Actinobacillus actinomycetemcomitans lipopolysaccharide (LPS-A. actinomycetemcomitans) could stimulate a murine macrophage cell line (RAW264.7 cells) to produce nitric oxide (NO). The cells were treated with LPS-A. actinomycetemcomitans or Escherichia coli LPS (LPS-Ec) for 24 h. The effects of N(G)-monomethyl-L-arginine (NMMA), polymyxin B and cytokines (IFN-gamma, TNF-alpha, IL-4 and IL-12) on the production of NO were also determined. The role of protein tyrosine kinase, protein kinase C and microtubulin organization on NO production were assessed by incubating RAW264.7 cells with genistein, bisindolylmaleide and colchicine prior to LPS-A. actinomycetemcomitans stimulation, respectively. NO levels from the culture supernatants were determined by the Griess reaction. The results showed that LPS-A. actinomycetemcomitans stimulated NO production by RAW264.7 cells in a dose-dependent manner, but was slightly less potent than LPS-Ec. NMMA and polymyxin B blocked the production of NO. IFN-gamma and IL-12 potentiated but IL-4 depressed NO production by LPS-A. actinomycetemcomitans-stimulated RAW264.7 cells. TNF-alpha had no effects on NO production. Genistein and bisindolylmalemaide, but not colchicine, reduced the production of NO in a dose-dependent mechanism. The results of the present study suggest that A. actinomycetemcomitans LPS, via the activation of protein tyrosine kinase and protein kinase C and the regulatory control of cytokines, stimulates NO production by murine macrophages.

Nitric oxide production by a murine macrophage cell line (RAW264.7) stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans.

Transforming growth factor-beta is a 25 kD polypeptide produced by both healthy and neoplastic cells. This cytokine effects the introduction of immune response, but its exact mechanism remains to be elucidated. In this paper the immuno-regulatory role of this cytokine on both the immunocompetent cells and accessory molecules is discussed. The growth factor-induced up and down regulation of the immune response suggest that transforming growth factor-beta can done some extent modulate certain pathological conditions, and hence suppressed production of this growth factor has potential benefits for bimodal immunotherapy.

The immunoregulatory roles of transforming growth factor beta.

Protective humoral immunity induced by surface-associated material from Actinobacillus actinomycetemcomitans in mice

Chronic inflammatory periodontal disease is known to be under the control of the immune response. However, the precise mechanism of the immunopathogenesis of this lesion has not yet been fully elucidated. In this review, the regulatory role of both lymphoid and non-lymphoid cells as well as cytokines and accessory molecules in the course of chronic inflammatory periodontal disease is discussed. Finally, based upon previous evidences, an attempt to establish a model of chronic inflammatory periodontal disease is made herein.

The immunopathology of chronic inflammatory periodontal disease

The aim of this study was to determine nitric oxide (NO) production of a murine macrophage cell line (RAW 264.7 cells) when stimulated with Porphyromonas gingivalis lipopolysaccharides (Pg-LPS). RAW 264.7 cells were incubated with i) various concentrations of Pg-LPS or Salmonella typhosa LPS (St-LPS), ii) Pg-LPS with or without L-arginine and/or NG-monomethyl-L-arginine (NMMA), an arginine analog or iii) Pg-LPS and interferon-gamma (IFN-gamma) with or without anti-IFN-gamma antibodies or interleukin-10 (IL-10). Tissue culture supernatants were assayed for NO levels after 24 h in culture. NO was not observed in tissue culture supernatants of RAW 264.7 cells following stimulation with Pg-LPS, but was observed after stimulation with St-LPS. Exogenous L-arginine restored the ability of Pg-LPS to induce NO production; however, the increase in NO levels of cells stimulated with Pg-LPS with exogenous L-arginine was abolished by NMMA. IFN-gamma induced independent NO production by Pg-LPS-stimulated macrophages and this stimulatory effect of IFN-gamma could be completely suppressed by anti-IFN-gamma antibodies and IL-10. These results suggest that Pg-LPS is able to stimulate NO production in the RAW 264.7 macrophage cell model in an L-arginine-dependent mechanism which is itself independent of the action of IFN-gamma.

L-arginine-dependent nitric oxide production of a murine macrophage-like RAW 264.7 cell line stimulated with Porphyromonas gingivalis lipopolysaccharide.

Endang Herminajeng

Papers

Nitric oxide production by a murine macrophage cell line (RAW264.7) stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans.

The immunoregulatory roles of transforming growth factor beta.

Protective humoral immunity induced by surface-associated material from Actinobacillus actinomycetemcomitans in mice

The immunopathology of chronic inflammatory periodontal disease

L-arginine-dependent nitric oxide production of a murine macrophage-like RAW 264.7 cell line stimulated with Porphyromonas gingivalis lipopolysaccharide.