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Interleukin 18 and Periodontal Disease

¹ School of Dentistry, Turbot Street, Brisbane 4000, Australia; and
² Faculty of Dentistry, University of Otago, Dunedin, New Zealand

View larger version (56K): [in this window] [in a new window]   Figure 1. Signal transduction pathways of IL-18. Intracellular activation of caspase (caspase-1 or caspase-1-like enzymes) in antigen-presenting cells is mediated through Toll-like receptor (TLR) or Fas signaling, respectively. Caspase-1 and the extracellular serine esterase PR-3 induce activation of biologically active interleukin (IL)-18 (18 kDa) by cleavage of its precursor, pro-IL-18 (24 kDa). If not inactivated by the extracellular IL-18-binding protein (IL-18BP), processed mature IL-18 mediates IL-18RC aggregation (IL-18 receptor complex, consisting of IL-18Rl, IL-18, CD48, and GPI), which binds to IL-18Rβ, leading to signal transduction by recruiting myeloid differentiation factor (MyD88), as well as IL-1 receptor-associated kinase (IRAK) in the effector cell. After phosphorylation, IRAK dissociates from the receptor complex and associates with tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which then leads to sequential activation of NF- B binding kinase (NIK), I-B kinases (IKK-1, IKK-2), and NF-B. Alternatively, the binding of IL-18 triggers the activation of Ras via a src family member of tyrosine kinases, the lymphocyte-specific tyrosine-specific protein kinase of 56 kDa (p56lck). Ras then sequentially activates Raf, mitogen-activated extracellular signal-regulated kinase-activating kinase (MEK) and mitogen-activated protein kinase (MAPK). This induces phosphorylation of MAPK, which is then translocated into the nucleus and phosphorylates CCAAT/enhancer-binding protein (C/EBP), enabling it to associate with the C/EBP binding site. Both NF-B and C/EBP induce gene transcription to produce further inflammatory mediators (such as IFN-, TNF-, IL-6, etc.). Adapted and modified from Tschoeke et al.(2006) and Fukushima et al.(2005).

View larger version (49K): [in this window] [in a new window]   Figure 2. IL-18 roles in adaptive and innate immunity. IL-18 is produced by several cells from the innate and adaptive immune systems, on stimulation by LPS, FasL, or interferons. The target cells of IL-18 include innate as well as adaptive immune cells. IL-18 exerts a synergistic effect with IL-12. IL-18 signals through a heterodimeric receptor, which recruits MyD88 and leads to the activation of the NF-B and AP-1 transcription factors (left inset). IL-18 signaling drives (top inset) the transcription of a set of cytokines (IFN-, TNF, IL-4, IL-6, IL-8), growth factors (GM-CSF]), and enzymes (NOS, COX-2, MMP3). However, IFN- is considered to be the key molecule induced by IL-18. MØ, macrophages; DC, dendritic cells; NOS, NO synthase; COX2, cyclo-oxygenase 2; MMP3, stromelysin; TIR, Toll/IL-1R domain; IL-18BP, IL-18-binding protein; IRAK, IL-1 receptor–associated kinase; TRAF6, TNF receptor–associated factor 6; IL-18R,β, and β chains of IL-18 receptor. Adapted and modified from Caligiuri et al.(2005).

Journal of Dental Research, Vol. 86, No. 7, 586-593 (2007)
DOI: 10.1177/154405910708600702


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