Cytokines and MMPs in RA

Cure Arthritis Naturally

Cure Arthritis Naturally

Get Instant Access

The chronic release of cytokines and matrix metalloproteinases (MMPs) is important in the pathogenesis of many chronic inflammatory diseases, especially RA. Since the discovery of cytokines in the 1960s [3], the important role of cytokines in modulating the immune system and disease has been gradually uncovered. Cytokines have multiple pleotrophic activities, acting at low concentrations usually over small distances for short periods of time. Their actions include modifying the expression of membrane proteins, altering proliferation, and secretion of effector molecules. With the cloning of cytokine cDNAs in the 1980s and 1990s and the generation of monoclonal antibodies to cytokines and their receptors has transformed cytokine research [4].

Les Hansenicas

Figure 2

Deformity of the hands in a rheumatoid arthritis (RA) patient

This disease causes synovial proliferation and joint destruction, usually in a symmetrical pattern. It is most visible in the small joints of the hands and feet.

Figure 2

Deformity of the hands in a rheumatoid arthritis (RA) patient

This disease causes synovial proliferation and joint destruction, usually in a symmetrical pattern. It is most visible in the small joints of the hands and feet.

In the RA joint/synovium increased levels of many cytokines have been documented, tumour necrosis factor (TNF)-a [5], IL (interleukin)-1 [6, 7], IL-6 [8], IL-8 [9], IL-10 [10], IL-12 [11], IL-15 [12] and IL-18 [13]. This is not a complete list, other factors are increased in RA but will not be discussed in this review, for example vascular endothelial growth factor (VEGF) which has a central role in the angiogenic process in RA [14]. TNF-a is predominantly produced by macrophages but also by lymphocytes, natural killer cells and mast cells. It can activate macrophages, endothelial cells, synovial fibroblasts, chondrocytes and osteophytes and can stimulate osteoclast differentiation, release of MMP, prostaglandins and cytokines and induce endothelial adhesion molecules expression.

Like TNF-a, IL-1 is considered a key proinflammatory cytokine in RA, with biological properties very similar to TNF-a. The effects of the two cytokines are often additive or synergistic, but at the local level IL-1 is a more potent inducer of MMPs. It also stimulates expression of eicosanoids, inducible nitric oxide synthase (iNOS), and receptor activator of NF-kB ligand (RANKL) among many other factors suggesting it a significant proinflammatory mediator in RA. IL-1 has two isoforms, IL-1a and IL-1p, a 17-kd protein mainly produced by monocytes and macrophages

[15] which was the first cytokine to be identified in the synovial fluid of RA patients

[16] suggesting it contributes to the pathogenesis of RA. Blockade of IL-1 in RA has modest anti-inflammatory effects and gives moderate joint protection [17], less profound than TNF-a blockade [18].

IL-6 is a cytokine produced by T cells, monocytes, macrophages, and synovial fibroblasts. It has pleiotrophic activity from differentiation of B cells into plasma cells, to activation of auto reactive T cells leading to the generation of autoantibod-ies [19]. It also upregulates intercellular adhesion molecule (ICAM) -1 expression [20], causes proliferation of synovial fibroblasts, activation of osteoclasts involved in bone resorption [21] and recruitment of immunocompetent cells into the synovium among other effects [22]. Blockade of IL-6 using anti-receptor monoclonal antibodies has a therapeutic effect in RA [23].

IL-1, TNF-a and IL-6 have been the major therapeutic targets in RA, but many other factors that play a role in the disease process leading to the chronic inflammation in RA are now being investigated. Although, IL-8 upregulates p2 integrins and induces neutrophil migration to inflamed tissue, use of anti-IL-8 antibodies has proved effective in animal models [24], but showed disappointing efficacy in RA trials and is no longer being investigated by Abgenix (http://www.abgenix.com/pro-ductdevelopment/?view=DevelopmentStrategy). IL-12 is a proinflammatory cytokine that helps regulate the equilibrium between T helper cell (Th) 1 and Th2 cells, and enhances cytotoxic T cell-mediated lysis and natural killer (NK) cell activity. IL-12 synergises with a variety of cytokines and induces the production of interferon (IFN)-y and proinflammatory cytokines [25]. Blockade of IL-12 p40 is beneficial in animal models [26], but as this subunit has more recently shown to be shared with IL-23, it is not clear whether IL-12 or IL-23 blockade produced this result. Another cytokine that could be a therapeutic target is IL-15. This activates T cells, in turn promoting the release of inflammatory cytokines including more IL-15, and stimulation of macrophages via a cell contact dependent manner to release TNF-a. IL-15 blockade is effective in animal models [27] and is presently in Phase II clinical studies [28].

IL-18 is produced by macrophages, articular chondrocytes, and osteoblasts [29, 30] and was originally identified as an IFN-y inducing factor [13]. The pro-form of IL-18 is cleaved by IL-1p-converting enzyme (caspase 1) to yield an active 18-kDa glycoprotein that is closely related to IL-1a and IL-1p [31]. It is capable of enhancing production of IL-1 and TNF-a and works in synergy with IL-12 and IL-15, inducing cell proliferation and increasing the production of other cytokines such as IFN-y, TNF-a, and granulocyte-macrophage colony-stimulating factor (GM-CSF)

by Th1 clones [29, 32]. In the murine collagen type II induced arthritis (CIA) model, mice expressing the murine gene encoding IL-18bp showed less severe inflammation or bone destruction in joints than mice not expressing IL-18bp [33]. IL-18bp (Tadekinig-a) is currently in a Phase IIa trial for RA (http://www.serono.com/prod-ucts/areas.jsp?major=1&minor=4).

The factors described so far are all proinflammatory mediators. Several anti-inflammatory mediators are also present in significant quantities in the synovium. These include IL-1 receptor antagonist (RA), IL-18 binding protein (bp), transforming growth factor (TGF)-P, soluble TNF-R, IL-10 and IL-4. IL-1RA specifically blocks the effects of IL-1 by binding the cell surface receptor IL-1R1 and preventing activation by IL-1p. IL-18bp is a naturally occurring molecule which binds IL-18 in the fluid phase preventing it from binding to cells. It is similar to the receptor, but is a secreted protein [34]. IL-10 produced by monocytes, macrophages, B cells and T cells and IL-4 produced by CD4+ Th2 cells, both act in vitro to inhibit T cell proliferation and decrease the production of cytokines including TNF-a, IL-1, IL-6, IL-8 and can increase the production IL-1RA [35-37]. However, in the disease state these inhibitory factors do not appear to be produced at adequate levels to neutralise the upregulated inflammatory molecules, as has been shown for IL-10 which on addition to rheumatoid cultures shows a decrease in the production of TNF-a and IL-1p [10].

Was this article helpful?

0 0
Arthritis Relief and Prevention

Arthritis Relief and Prevention

This report may be oh so welcome especially if theres no doctor in the house Take Charge of Your Arthritis Now in less than 5-Minutes the time it takes to make an appointment with your healthcare provider Could you use some help understanding arthritis Maybe a little gentle, bedside manner in your battle for joint pain relief would be great Well, even if you are not sure if arthritis is the issue with you or your friend or loved one.

Get My Free Ebook


Post a comment