Signalling, inflammation and arthritis: Crossed signals: The role of interleukin-15 and -18 in autoimmunity

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
Rheumatology (Oxford, England) (Impact Factor: 4.48). 09/2008; 47(9):1269. DOI: 10.1093/rheumatology/ken257


Several cytokines are involved in the complex processes ultimately leading to autoimmune diseases. In a preceding review,
we have already discussed the role of the IL-12 and -17 families of cytokines. This review is focused on IL-15 and -18. Both
these molecules have pro-inflammatory activity and act on many cell types and because of their broad spectrum of activity
they play an important role in autoimmunity and disease pathogenesis. Their biological activity is ultimately regulated by
the signalling cascades set into motion within their target cells. In this second review, we will, once again, describe the
signal transduction pathways activated by these two cytokines and focus on how this relates to the pathogenesis of autoimmune
diseases. We will also describe some of the therapeutic approaches that are being investigated to curtail the pro-inflammatory
activities of these two molecules.

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    • "Interleukin-15 (IL-15), initially described as a T cell growth factor, is a 14-15 kDa innate response cytokine that regulates T and natural killer (NK) cell activation and proliferation [5]. As a proinflammatory cytokine, IL-15 is believed to be implicated in pathophysiology of arthritis through multiple mechanisms, especially for patients with rheumatoid arthritis (RA) [6]. Blockade of IL-15 has been met with therapeutic success in RA patients [7]. "
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    ABSTRACT: Background. Inflammation plays a crucial role in the development and progression of osteoarthritis (OA). Interleukin-15 (IL-15) is a well-known proinflammatory cytokine. Objective. We aimed at evaluating the relationship between serum IL-15 levels and the severity of pain as well as radiographic progression in patients with knee OA. Methods. Two hundred and twenty-six OA patients and 106 controls were enrolled in this study. The symptomatic/radiological severity of OA was assessed by the Western Ontario McMaster University Osteoarthritis Index- (WOMAC-)pain scores/Kellgren-Lawrence (KL) grading system. Serum IL-15 levels were measured by enzyme-linked immunosorbent assay (ELISA). Results. Serum IL-15 levels were significantly higher in OA patients compared with controls. Serum IL-15 levels were independently and positively correlated with WOMAC-pain scores but not KL grades in OA patients. Conclusions. We demonstrated that increased serum IL-15 levels were independently correlated with self-reported greater pain in knee OA patients. These results suggest that IL-15 might play a crucial role in the pathogenesis of OA related pain and therapeutic interventions by blocking IL-15 signaling pathways to delay the degenerative process of OA related pain which warrants further investigations.
    Disease markers 09/2013; 35(3):203-6. DOI:10.1155/2013/176278 · 1.56 Impact Factor
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    • "We observed that the de novo expression of NCRs (and of NKp30 in particular) correlates with cell proliferation, confirming once again that the NCR induction is associated with cell activation and division. In fact, our results indicate that NCR induction is dependent on both TCR stimulation and the presence of γc cytokines such as IL-15, which is present at high levels during the course of several inflammatory conditions (Carroll et al., 2008). Moreover, the hypothesis that the induced expression of NCRs is limited to certain populations of T cells carrying a particular TCR (Jabri et al., 2002; Meresse et al., 2006; Stewart et al., 2007; Yu et al., 2011) is also supported by our data showing that NCRs can only be induced on γδ T cells expressing the Vδ1 but not the Vδ2 TCR chain. "
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    ABSTRACT: Natural cytotoxicity receptors (NCRs) have been classically defined as activating receptors delivering potent signals to Natural Killer (NK) cells in order to lyze harmful cells and to produce inflammatory cytokines. Indeed, the elicitation of NK cell effector functions after engagement of NCRs with their ligands on tumor or virus infected cells without the need for prior antigen recognition is one of the main mechanisms that allow a rapid clearance of target cells. The three known NCRs, NKp46, NKp44, and NKp30, comprise a family of germ-line encoded Ig-like trans-membrane (TM) receptors. Until recently, NCRs were thought to be NK cell specific surface molecules, thus making it possible to easily distinguish NK cells from phenotypically similar cell types. Moreover, it has also been found that the surface expression of NKp46 is conserved on NK cells across mammalian species. This discovery allowed for the use of NKp46 as a reliable marker to identify NK cells in different animal models, a comparison that was not possible before due to the lack of a common and comprehensive receptor repertoire between different species. However, several studies over the recent few years indicated that NCR expression is not exclusively confined to NK cells, but is also present on populations of T as well as of NK-like lymphocytes. These insights raised the hypothesis that the induced expression of NCRs on certain T cell subsets is governed by defined mechanisms involving the engagement of the T cell receptor (TCR) and the action of pro-inflammatory cytokines. In turn, the acquisition of NCRs by T cell subsets is also associated with a functional independence of these Ig-like TM receptors from TCR signaling. Here, we review these novel findings with respect to NCR-mediated functions of NK cells and we also discuss the functional consequences of NCR expression on non-NK cells, with a particular focus on the T cell compartment.
    Frontiers in Immunology 03/2013; 4(69):69. DOI:10.3389/fimmu.2013.00069
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    • "Signaling through either the TCR or the IL - 12 and IL - 18 recep - tors results in the activation of a group of transcription factors that partially , but not completely , overlap ( Carroll et al . , 2008 ; Smith - Garvin et al . , 2009 ; Verdeil et al . , 2006 ; Watford et al . , 2004 ) . TCR ligation and costimulation lead to phosphorylation of p56 lck ( Lck ) , zeta - chain - associated protein kinase 70 ( ZAP70 ) , and linker for activation of T cells ( LAT ) , ultimately leading to the activation of a variety of transcription factor"
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    ABSTRACT: During infection, CD8(+) T cells not only respond to antigenic signals through their T cell receptor (TCR) but also incorporate inflammatory signals from cytokines produced in the local infected microenvironment. Transient TCR-mediated stimulation will result in programmed proliferation that continues despite removal of the antigenic stimulus, but it remains unclear whether brief exposure to specific cytokines will elicit similar effects. Here, we have demonstrated that brief stimulation of memory T cells with interleukin-12 (IL-12) and interleukin-18 (IL-18) results in tightly regulated programmed proliferation, in addition to acquisition of enhanced virus-specific cytokine production and cytolytic activity. CD8(+) T cells briefly exposed to IL-12 and IL-18 in vitro showed improved antiviral activity in vivo, as demonstrated by increased proliferation and reduced viremia. These results indicate that even transitory exposure to inflammatory cytokines can provide a selective advantage to infiltrating CD8(+) T cells by triggering a developmental program that is initiated prior to direct contact with virus-infected cells.
    Immunity 12/2012; 38(1). DOI:10.1016/j.immuni.2012.09.019 · 21.56 Impact Factor
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