RHEUMATOID ARTHRITIS: ROLE OF PRO-INFLAMMATORY CYTOKINES INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR

S. Martinotti

Affiliation: Department of Medical, Oral and Biotechnological Sciences, University of Chieti, Chieti, Italy

Rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune inflammatory arthropathy, driven by auto-antibodies, which are deposited as immune complexes in various organs and tissues, affects approximately 1% of the human population (1). RA is a chronic inflammatory disease characterized by extensive synovitis which leads to the erosion of articular cartilage, marginal bone and joint destruction (2). Inflammatory cytokines participate in RA in perpetuation of the disease which provokes systemic disorder. An imbalance in the cytokine network may lead to inflammation and autoimmune diseases including RA (3). In fact, the autoimmune process in RA depends on the activation of immune cells, which secrete cytokines that participate in the inflammatory state (4). These cytokines cause a dramatic impact on metabolism, vascular dysfunction, and endothelial and immunological homeostasis which is an important process implicated in maintaining a physiological bone mass. The pathological effects that occur in RA are mediated by immune cells that produce inflammatory cytokines, giving rise to the phenomenon of osteoimmunology, a chapter of medicine that studies the interaction between immunity and bone dynamics. In RA, there is the presence of the rheumatoid factor, consisting of antibodies related to the severity of the disease, with activation of the osteoclasts and their precursors. Inhibition of the production of these antibodies and inflammation can certainly have a therapeutic effect. In RA, the inflammatory process caused by cytokines leads to bone damage throughout the body. Inflammatory cytokines mediate the differentiation of osteoclasts involved in bone resorption (5). Among the cytokines that participate in RA, an important role is played by tumor necrosis factor (TNF) and interleukin (IL)-1 which participate in the destruction of bone and cartilage with the activation of immune cells such as mast cells (MCs) and macrophages (6). Several lines of evidence support the importance of IL-1β (2, 3) in RA, but less is known about the populations of innate immune cells that contribute to the production of IL-1β in this disorder. Certainly the cells of innate immunity, such as macrophages and MCs, intervene in a decisive manner.

The inflammatory response may involve the generation of inflammatory cytokines which may mediate the activation of immune/inflammatory cells such as macrophages, lymphocytes, neutrophils and MCs (7). These cells, after activation, release many different cytokines and chemokines which are mediators of the immune responses and are associated with RA. In the synovial fluid of RA patients, numerous chemokines are found that regulate the trafficking of leucocytes that are upregulated. In these liquids, the chemokines CCL19 and CCL21 have been found which recruit dendritic cells (DC) in the synovial fluid and immature DCs (8-9).

MCs emerge as important elements of innate immunity against invading pathogens producing stored products, such as histamine and tryptase, but also pro-inflammatory cytokines such as IL-1. In RA, MCs contribute to acute arthritis especially in the early stages (7).

 IL-1, through IL-1 receptor type 1 (IL-1RI), induces the upregulation of inflammatory molecules, which may lead to the generation of arachidonic acid cascade with a release of inflammatory compounds including prostaglandins, leukotrienes and lipoxines. In fact, in RA where the level of IL-1 is high, the products of this cascade are also increased (10). It has been reported that IL-1 inhibitors show therapeutic benefits in RA experimental models and in humans.

Interleukin-1

            IL-1 is an inflammatory cytokine involved in multiple diverse biological activities, which plays a crucial role in many diseases such as cancer, fever, metabolic disorders, skin and autoimmune diseases (11). IL-1-beta, which is the most studied of the IL-1 family members, acts by binding to its ILR1 receptor to which IL-1R3 bind a complex that allows the intervention of TIR and recruitment of MyD88, and initiating the pro-inflammatory pathway. It has been reported that IL-1 is involved in several rheumatic diseases and in inflammatory processes, including RA (12). It has been found that IL-1 is not only present in macrophages, but also in fibroblasts, synovial cells and keratinocyte cells, and other cell types. IL-1 is strongly linked to RA where it causes the loss of collagen, narrowing of the joint space, destruction of the cartilaginous tissue and systemic manifestations. IL-1 also activates arachidonic acid cascade with stimulation of PGE2 and thromboxane A2 from neutrophil granulacytes.

IL-1 is present in synovial fluid, cartilage and chondrocytes of patients with RA, provoking the induction of proteases (such as metalloproteinase) and cartilage damage. It has been reported that in animal experimental model, use of inflammatory IL-1 family inhibitors reduces inflammation and loss of proteoglycans in cartilage.

Therefore, IL-1 inflammatory cytokines orchestrate systemic inflammatory responses, including RA, and can have an important effect on the quality of life. IL-1 is an important mediator of a spectrum of inflammatory diseases, and has its own antagonist called IL-1Ra, which blocks the effect of IL-1 by binding to the IL-1R1 receptor. In addition, some IL-1 family members, including IL-36Ra, IL-37 and IL-38, perform an anti-inflammatory activity, with important therapeutic promises in RA.

However, the role of IL-1 family members in RA, contributing in eithera  pro-inflammatory or an anti-inflammatory manner is still unclear, and therefore remains to be determined (12).

Tumor necrosis factor

In 1975, Carswell et al. described for the first time TNF, a cytokine found in the serum of infected mice treated with bacillus of Calmette-Guerin. Upon Sipopolysaccharide stimulation, macrophages can release TNF (13).

TNF has emerged as an important pro-inflammatory cytokine that plays a critical role in the pathogenesis of autoimmune diseases, including RA. This cytokine is an important factor in autoimmune diseases where other cytokines/chemokines play a relevant and active role. TNF, via IgE-dependent mechanisms, is produced by various non-immune and immune cells, including MCs, that release this cytokine from both stored preformed pool in the granules and newly synthesized TNF through mRNA. Elevated levels of TNF-alpha are frequently observed in the synovial fluid of RA subjects emphasizing the importance of TNF in the initiation of rheumatic inflammation and the generation of tissue hyper-responsiveness.

TNF may be a novel therapeutic target in acute and chronic diseases, including RA. Antagonists targeting TNF have been developed to neutralize its effects and have been shown to be effective in treating patients with RA, although the collateral immunological effects are not excluded.  Again, recent studies have shown that TNF can also be suppressed by some IL-1 inhibitors such as IL-37 and IL-38, with therapeutic potential in RA (12). However, the full biological roles of TNF and the molecular mechanisms regulating its production, remain to be defined.

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