RHEUMASEARCH

IL-1, IL-18, and IL-33 families of cytokines.

Immunol Rev. 2008 Jun;223:20-38.
 
SUMMARY: The interleukin-1 (IL-1), IL-18, and IL-33 families of cytokines are related by mechanism of origin, receptor structure, and signal transduction pathways utilized. All three cytokines are synthesized as precursor molecules and cleaved by the enzyme caspase-1 before or during release from the cell. The NALP-3 inflammasome is of crucial importance in generating active caspase-1. The IL-1 family contains two agonists, IL-1alpha and IL-1beta, a specific inhibitor, IL-1 receptor antagonist (IL-1Ra), and two receptors, the biologically active type IL-1R and inactive type II IL-1R. Both IL-1RI and IL-33R utilize the same interacting accessory protein (IL-1RAcP). The balance between IL-1 and IL-1Ra is important in preventing disease in various organs, and excess production of IL-1 has been implicated in many human diseases. The IL-18 family also contains a specific inhibitor, the IL-18-binding protein (IL-18BP), which binds IL-18 in the fluid phase. The IL-18 receptor is similar to the IL-1 receptor complex, including a single ligand-binding chain and a different interacting accessory protein. IL-18 provides an important link between the innate and adaptive immune responses. Newly described IL-33 binds to the orphan IL-1 family receptor T1/ST2 and stimulates T-helper 2 responses as well as mast cells.
 

A systematic review of infliximab in the treatment of early rheumatoid arthritis

Ther Clin Risk Manag. 2007 Oct;3(5):905-11.
 
BACKGROUND: Several health authorities have recently revised the indication of infliximab (IFX) to include the treatment of early rheumatoid arthritis (RA). The aim of this systematic review of the literature was to appraise the efficacy, safety, and cost-effectiveness of early therapy with IFX. METHODS: We identified published clinical trials from 1966 to May 2006. We included randomized clinical trials (RCTs) in RA with disease duration of less than 3 years comparing the treatment of methotrexate-IFX (MTX-IFX) with methotrexate-placebo (MTX-placebo). RESULTS: A total of 8 studies met inclusion criteria. Three studies reported redundant data regarding the vdH Sharp Score. Out of the 5 remaining studies, 4 analyzed structural joint destruction (vdH Sharp Score) and demonstrated a significant reduction in radiographic damage progression in favor of the combination of MTX-IFX compared with MTX-placebo (-4.1 vdH Sharp Score units (95% CI: 3.5; 4.6). Three studies also displayed a benefit of MTX-IFX on functional outcomes of RA (HAQ score) and disease activity measures (DAS, ACR response criteria), although less markedly.
CONCLUSIONS: Although data might be skewed because of only 2 existing large studies with concordant data, results from RCTs demonstrate improved efficacy of the combination MTX-IFX compared with MTX-placebo in early RA. However, many early RA patients probably do not require the addition of IFX to achieve a satisfying clinical and radiological course. So far, no evidence has established the superiority of MTX-IFX over MTX-prednisone or other combinations of traditional disease-modifying anti-rheumatic agents.
 

The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33.

Cytokine. 2008 Jun;42(3):358-64. Epub 2008 May 2.
 
Interleukin (IL)-33 (or IL-1F11) was recently identified as a ligand for the orphan IL-1 receptor family member T1/ST2 (ST2). IL-33 belongs to the IL-1 cytokine family and, upon binding to ST2, induces intracellular signals similar to those utilized by IL-1. The effects of other IL-1 family cytokines are mediated by their binding to a specific receptor and the recruitment of a co-receptor required for elicitation of signaling. The aim of this study was to characterize the co-receptor involved in IL-33 signaling. Immunoprecipitation confirmed that IL-33 specifically binds ST2 and revealed that cellular IL-1 receptor accessory protein (AcP) associates with ST2 in a ligand-dependent manner. Receptor binding measurements demonstrated that the affinity of mouse (m)IL-33 for ST2 is increased by 4-fold in presence of AcP. IL-33 dose-dependently stimulated IL-6 secretion from wild-type (WT) mast cells, while no effect of IL-33 was observed with mast cells derived from AcP-deficient mice. Finally, soluble (s) ST2-Fc and sAcP-Fc acted synergistically to inhibit IL-33 activity. These observations identify AcP as a shared co-receptor within the IL-1 family that is essential for IL-33 signaling and suggest a novel role for sAcP in modulating the activity of IL-33.
 

At the horizon of innovative therapy in rheumatology: new biologic agents.

Curr Opin Rheumatol. 2008 May;20(3):269-75.
 
PURPOSE OF REVIEW: To review the rational and the results regarding the use of novel biologic agents in inflammatory rheumatic diseases.
RECENT FINDINGS: Recent findings show that excessive IL-1 processing and release contribute to different rheumatic conditions, including periodic fever syndromes, systemic-onset juvenile idiopathic arthritis, adult Still's disease, and crystal-induced arthritis. Preliminary results indicate that administration of IL-1 receptor antagonist and other IL-1 inhibitors improves these conditions. IL-6 also plays a major role in the control of inflammatory responses. Several clinical trials have shown that inhibition of IL-6 by a monoclonal antibody against its receptor is efficacious in rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis patients. Accumulating evidence indicates that other cytokines, including IL-15, IL-18, and IL-21 may also play an important role in rheumatoid arthritis. Several signaling pathways involved in the immune and inflammatory responses may also constitute novel targets. Preliminary data on an agent targeting the Janus kinase/Signal transducer and activators of transcription pathway are encouraging.
SUMMARY: Beyond tumor necrosis factor alpha targeting, the use of inhibitors against other cytokines and cytokine-induced intracellular responses is leading to a promising therapy in the future.
 

The effectiveness of leflunomide as co-therapy of TNF inhibitors in rheumatoid arthritis. A population based study.

Ann Rheum Dis. 2008 Jan 29. [Epub ahead of print]
 
BACKGROUND:Randomized trials have demonstrated that the efficacy of anti-TNF agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are commonly prescribed with other disease modifying antirheumatic drugs (DMARDs) than MTX, however their effectiveness in combination with anti-TNF agents is not well established.
OBJECTIVE: To compare the effectiveness of leflunomide (LEF) and other conventional DMARDs with MTX as co-therapy to anti-TNF agents in RA.
METHODS: All patients on anti-TNF agents and conventional DMARDs within the SCQM-RA database were included (N=1218) and categorized according to the type of co-therapy into anti-TNF+MTX (N=842), anti-TNF+LEF (N=260) and anti-TNF+other DMARDs (N=116). Drug discontinuation rates and incidence of toxic side effects were analyzed using Cox proportional hazards models. Progression of radiographic damage, the evolution of functional disability and the improvement of RA disease activity were analyzed using longitudinal regression models, adjusting for potential confounders.
RESULTS: The overall discontinuation rates of anti-TNF and conventional DMARD combination therapies were relatively high with a median survival of only 16 months (IQR: 10 - 37), but they did not differ between the three regimen (p=0.69). The progression of radiographic damage (p=0.77), functional disability (p=0.09) and RA disease activity (p=0.33) were also similar between the different regimen. In addition, no significant difference in the frequency of adverse events emerged. CONCLUSION: Overall these results suggest that LEF and potentially other conventional DMARDs offer an effective and safe alternative to MTX as co-therapy in combination with anti-TNF agents.
 

The proinflammatory cytokine response to Chlamydia trachomatis elementary bodies in human macrophages is partly mediated by a lipoprotein, the macrophage infectivity potentiator, through TLR2/TLR1/TLR6 and CD14.

J Immunol. 2008 Jan 15;180(2):1158-68.
 
Chlamydiae components and signaling pathway(s) responsible for the production of proinflammatory cytokines by human monocytes/macrophages are not clearly identified. To this aim, Chlamydia trachomatis-inactivated elementary bodies (EB) as well as the following seven individual Ags were tested for their ability to induce the production of proinflammatory cytokines by human monocytes/macrophages and THP-1 cells: purified LPS, recombinant heat shock protein (rhsp)70, rhsp60, rhsp10, recombinant polypeptide encoded by open reading frame 3 of the plasmid (rpgp3), recombinant macrophage infectivity potentiator (rMip), and recombinant outer membrane protein 2 (rOmp2). Aside from EB, rMip displayed the highest ability to induce release of IL-1beta, TNF-alpha, IL-6, and IL-8. rMip proinflammatory activity could not be attributed to Escherichia coli LPS contamination as determined by the Limulus Amoebocyte lysate assay, insensitivity to polymyxin B (50 microg/ml), and different serum requirement. We have recently demonstrated that Mip is a "classical" bacterial lipoprotein, exposed at the surface of EB. The proinflammatory activity of EB was significantly attenuated in the presence of polyclonal Ab to rMip. Native Mip was able to induce TNF-alpha and IL-8 secretion, whereas a nonlipidated C20A rMip variant was not. Proinflammatory activity of rMip was unaffected by heat or proteinase K treatments but was greatly reduced by treatment with lipases, supporting a role of lipid modification in this process. Stimulating pathways appeared to involve TLR2/TLR1/TLR6 with the help of CD14 but not TLR4. These data support a role of Mip lipoprotein in pathogenesis of C. trachomatis-induced inflammatory responses.
 

Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells.

Cytokine. 2007 Dec;40(3):216-25. Epub 2007 Nov 19.
 
IL-33 (or IL-1F11) was recently identified as a ligand for the previously orphaned IL-1 family receptor T1/ST2. Previous studies have established that IL-33 and T1/ST2 exert key functions in Th2 responses. In this study, we demonstrate that IL-33 induces the production of pro-inflammatory mediators in mast cells. IL-33 dose and time-dependently stimulated IL-6 secretion by P815 mastocytoma cells and primary mouse bone marrow-derived mast cells (BMMC). This effect was dependent on T1/ST2 binding. In addition, IL-33 also induced IL-1beta, TNF-alpha, MCP-1, and PGD2 production in BMMC. By RNase protection assay, we demonstrated that IL-33 increased IL-6 and IL-1beta mRNA expression. These effects of IL-33 appeared to occur independently of mast cell degranulation, The results of this study show for the first time that IL-33, a novel member of the IL-1 family of cytokines, stimulates the production of pro-inflammatory mediators by mast cells in addition to its effect on T helper 2 responses. These findings open new perspectives for the treatment of inflammatory diseases by targeting IL-33.