Expression of interleukin-18 in muscle tissue of patients with polymyositis or dermatomyositis and effects of conventional immunosuppressive treatment.

Objectives: To investigate the expression of IL-18 in symptomatic and asymptomatic muscle tissues of patients with PM and DM and the effects of conventional immunosuppressive treatment on such expression.

Methods: Two cohorts of patients were included in this study. The first cohort consisted of 10 new-onset myositis patients.

The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release.

Objectives: Macrophages are central to the inflammatory processes driving rheumatoid arthritis (RA) synovitis. The molecular pathways that are induced in synovial macrophages and thereby promote RA disease pathology remain poorly understood.

Methods: We used microarray to characterise the transcriptome of synovial fluid (SF) macrophages compared with matched peripheral blood monocytes from patients with RA (n=8).

The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17-producing cellular network at multiple sites.

Objective: Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62.

FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25- responder T cells, but not CD4+CD25+ regulatory T cells.

Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype.

Phosphodiesterase 4 (PDE4) regulation of proinflammatory cytokine and chemokine release from rheumatoid synovial membrane.

Background: The cAMP-metabolising enzyme, phosphodiesterase 4 (PDE4), has been implicated in a number of immune responses, including tumour necrosis factor α (TNFα) production. To date, few data have directly addressed whether synovial cytokine and chemokine production is modified by PDE4.

Objective: Using specific PDE4 inhibitors, roflumilast plus two novel inhibitors, INH 0061 and INH 0062, the authors studied the effect of PDE4 inhibition on proinflammatory cytokine and chemokine release from primary rheumatoid arthritis (RA) synovial digest suspensions and in a macrophage T cell co-culture assay system.

Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies using a novel proteinase-activated receptor 2 antagonist.

Objective: Serine proteinases activate the G protein-coupled receptor, proteinase-activated receptor 2 (PAR-2), via cleavage and exposure of a tethered ligand. PAR-2 is known to exert proinflammatory actions in a murine model of arthritis, since PAR-2-deficient mice exhibit strikingly reduced articular inflammation. This study was undertaken to examine synovial PAR-2 expression and to determine the effect of a novel PAR-2 antagonist on synovial cytokine production, in order to investigate the hypothesis that PAR-2 plays a critical role in the pathogenesis of rheumatoid arthritis (RA).

Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis.

Dendritic cells (DCs) comprise heterogeneous subsets of professional antigen-presenting cells, linking innate and adaptive immunity. Analysis of DC subsets has been hampered by a lack of specific DC markers and reliable quantitation assays. We characterised the immunophenotype and functional characteristics of psoriatic arthritis (PsA)-derived and rheumatoid arthritis (RA)-derived myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to evaluate their potential role in arthritis.

Expression and alternative processing of IL-18 in human neutrophils.

Interleukin-18 (IL-18), a member of the IL-1 cytokine superfamily, is an important regulator of both innate and acquired immune responses. We demonstrate here constitutive expression of IL-18 by human neutrophils. Unexpectedly, we observed that neutrophils from peripheral blood or rheumatoid synovial compartments contained not only pro and mature IL-18, but also several novel smaller-molecular-weight IL-18-derived species.

Targeting cytokines beyond tumor necrosis factor-alpha and interleukin-1 in rheumatoid arthritis.

Targeting tumor necrosis factor-a has proven of considerable value in treatment for rheumatoid arthritis, with substantial benefits achieved in a proportion of treated patients. However, a significant number of patients do not achieve sufficient improvement and as a result there remains considerable unmet clinical need. A number of cytokines have recently been described with proinflammatory activity in rheumatoid arthritis synovitis, including interleukin (IL)-6, IL-12, IL-15, and IL-18.

Inhibition of neutrophil function by the Kaposi's sarcoma-associated herpesvirus vOX2 protein.

Kaposi's sarcoma is multifactorial, involving Kaposi's sarcoma-associated herpesvirus (KSHV) infection and immune dysfunction. A KSHV protein (vOX2), fused with the Fc domain of human immunoglobulin G1 to create vOX2:Fc, suppressed neutrophil oxidative burst and inhibited the production of pro-inflammatory chemokines (IL-8 and monocyte chemoattractant protein 1) by monocyte/macrophage cells. vOX2:Fc suppressed the acute inflammatory response in mice in which neutrophil-mediated inflammation was induced by carrageenan.

Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study.

Objective: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA.

Methods: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15.

Prior elevation of IL-18 promotes rapid early IFN-gamma production during staphylococcal infection.

Systemic Staphylococcus aureus infection is associated with significant morbidity and mortality arising from both bacterial and host immune factors. IL-18 is a pro-inflammatory cytokine of the IL-1 superfamily that exhibits broad functional effects in innate and acquired immune responses and which has been found in high levels in several chronic inflammatory and autoimmune diseases. Over-expression of IL-18 may promote early resolution of infection or could promote a detrimental exaggerated immune response.

Interleukin-18: a therapeutic target in rheumatoid arthritis?

Interleukin 18 (IL-18), a member of the IL-1 superfamily of cytokines has been demonstrated to be an important mediator of both innate and adaptive immune responses. Several reports have implicated its role in the pathogenesis of rheumatoid arthritis (RA). Although biologic therapy is firmly established in the treatment of a number of inflammatory diseases including RA, partial and non-responder patients constitute residual unmet clinical need.

Targeting cytokines beyond tumor necrosis factor-alpha and interleukin-1 in rheumatoid arthritis.

Targeting tumor necrosis factor-a has proven of considerable value in treatment for rheumatoid arthritis, with substantial benefits achieved in a proportion of treated patients. However, a significant number of patients do not achieve sufficient improvement and as a result there remains considerable unmet clinical need. A number of cytokines have recently been described with proinflammatory activity in rheumatoid arthritis synovitis, including interleukin (IL) -6, IL-12, IL-15, and IL-18.

Interleukin-15: a new cytokine target for the treatment of inflammatory diseases.

Interleukin (IL)-15 is a pleiotropic pro-inflammatory cytokine that is expressed in several inflammatory disorders, including rheumatoid arthritis, psoriasis and pulmonary inflammatory diseases. IL-15 promotes activation of T cells, neutrophils and macrophages, and is critical to dendritic cell function in several model systems. Recent emerging data suggest that IL-15 may serve as a useful therapeutic target across a range of disease states.

Inducing experimental arthritis and breaking self-tolerance to joint-specific antigens with trackable, ovalbumin-specific T cells.

The importance of T cell Ag specificity and Th1 vs Th2 phenotype in synovial inflammation remains controversial. Using OVA-specific TCR transgenic T cells from DO11.10 mice, we demonstrate that mice receiving Th1, but not Th2, cells display a transient arthritis following immunization that is characterized by synovial hyperplasia, cellular infiltration, and cartilage erosion.

The anti-inflammatory potential of the filarial nematode secreted product, ES-62.

Filarial nematodes achieve long-term infection via modulation of the host immune system. Although human infection can result in severe pathology, the majority of infected individuals exhibit little evidence of this. Analysis of the immune response during infection indicates that the apparently healthy majority have an anti-inflammatory phenotype and it has been speculated that this may contribute to maintenance of host health.

A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62.

Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature.

Interleukin-18.

Interleukin-18 (IL-18), a recently described member of the IL-1 cytokine superfamily, is now recognized as an important regulator of innate and acquired immune responses. IL-18 is expressed at sites of chronic inflammation, in autoimmune diseases, in a variety of cancers, and in the context of numerous infectious diseases. This short review will describe the basic biology of IL-18 and thereafter address its potential effector and regulatory role in several human disease states including autoimmunity and infection.

A novel anti-inflammatory role for simvastatin in inflammatory arthritis.

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo.

Chemoattraction of human T cells by IL-18.

Cell locomotion is crucial to the induction of an effective immune response. We report here the chemoattraction of CD4(+) T cells by IL-18, a member of the IL-1 cytokine family. Recombinant IL-18 increased the proportion of T cells in polarized morphology in vitro and stimulated their subsequent invasion into collagen gels in an IL-18 concentration gradient-dependent manner.

Novel pathways that regulate tumor necrosis factor-alpha production in rheumatoid arthritis.

Clinical intervention studies have clearly shown the benefit in suppressing tumor necrosis factor-alpha (TNF-alpha) rheumatoid arthritis (RA). In consequence, considerable interest has arisen in those pathways that in turn regulate TNF-alpha production, because they may offer further possible therapeutic targets. Several candidate pathways are currently being investigated.