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A New Inflammatory Cytokine on the Block: Re-thinking Periodontal Disease and the Th1/Th2 Paradigm in the Context of Th17 Cells and IL-17

¹ Department of Oral Biology, School of Dental Medicine, 36 Foster Hall, 3435 Main St., and
² Department of Microbiology & Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA; and
³ Department of Periodontics/Oral Health and Systemic Disease and
⁴ Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA

View larger version (33K): [in this window] [in a new window]   Figure 1. Th cell differentiation and the extended IL-12 superfamily. (A) The 4 major T helper cell subsets. Naïve CD4+ T-cells are stimulated by antigen in the context of an antigen-presenting cell (APC) to differentiate into specific effector fates. The classic Th1 and Th2 populations are driven by IL-12 (composed of the IL-12p35 and IL-12/23p40 subunits) and IL-4, respectively. The hallmark Th1 cytokine is IFN, which activates macrophages, cytotoxic T-cells, and NK cells, as well as driving anti-viral signals in target cells. In addition, IFN provides a positive feedback signal to reinforce Th1 development by up-regulating the IL-12 receptor. Signals from Th1 cytokines also inhibit Th2 and Th17 differentiation. IL-4 is the signature cytokine of the Th2 population, and provides an analogous positive reinforcement signal to drive expansion of this lineage. Th17 cells are driven to differentiate by TGFβ, IL-6, IL-1, and IL-21 (reviewed by Weaver et al., 2007). In addition, IL-23 (composed of IL-12/23p40 and IL-23p19) is a key expansion and pathogenicity factor (Ghilardi and Ouyang, 2007). Th17 cells provide important immunity against extracellular pathogens through activation of innate inflammation events, but are also the key Th cell contributors to autoimmunity in various settings (Kolls and Linden, 2004; Gaffen et al., 2006; Kramer and Gaffen, 2007). The immunosuppressive T regulatory (Treg) cell population is driven to develop in opposition to Th17, since signals from TGFβ in the absence of STAT3 (via IL-6 and/or IL-21) serve to drive this lineage. IL-2 is an important cytokine in expanding this lineage, while simultaneously inhibiting Th17 development (Laurence et al., 2007). (B) The extended IL-12 cytokine family. The various components of IL-12, IL-23, IL-27, and the newly-described IL-35 are depicted (Collison et al., 2007; Ghilardi and Ouyang, 2007). (C) Activators and inhibitors of Th17 differentiation. Various cytokines and transcription factors can either enhance or inhibit Th17 development (Weaver et al., 2007).

View larger version (33K): [in this window] [in a new window]   Figure 2. Concepts in periodontal disease pathogenesis. In the linear model (A), the bacteria are seen as initiators of the inflammatory process. Disease progression depends exclusively on the host response, which offers a target (*) for therapeutic intervention (e.g., anti-inflammatory agents) (Salvi and Lang, 2005). The circular model (B) contends that bacteria are necessary for both initiation and progression of the disease, by constantly shaping the T-cell response through differential TLR-mediated activation of APC and secreted cytokines. The innate and adaptive host response, in turn, determines the fate of the infection, and consequently whether inflammation will progress to disease or be controlled. Although the role of the individual effector Th subsets is debatable, Th2 cells have been associated with non-protective antibody responses and progressive periodontal lesions, and Th1 with stable lesions (indicated by an inhibitory sign against disease progression; ) (Gemmell et al., 2002). Th1 cells are thought to protect through IL-12/IFN-stimulated cell-mediated immunity (Alayan et al., 2007b; Hajishengallis et al., 2007) and by inhibition of osteoclastogenesis (Gowen et al., 1986; Horwood et al., 2001). In contrast, Th17 cells have been implicated as a specialized osteoclastogenic subset that links T-cell activation to bone loss (Sato et al., 2006). Contrary to this potentially destructive role, IL-17 produced by this subset has been associated with neutrophil-mediated control of the bacterial challenge (Yu et al., 2007). Periodontal bone loss and soft-tissue alterations offer new niches for colonization (generation of deep periodontal pockets) and thus facilitate bacterial overgrowth; this presents increased challenge and reinforces the circular process or, metaphorically, the ongoing vicious cycle. This model offers three types of targets for therapeutic intervention: antimicrobial (*1), TLR-based modulation of APC responses (*2), and cytokine-based control of T-cell activation (*3).

Journal of Dental Research, Vol. 87, No. 9, 817-828 (2008)
DOI: 10.1177/154405910808700908


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