Interleukin-6: Pathophysiology and Clinical Implications in Rheumatoid Arthritis

The realization that IL-6 is implicated in many pathologic features of RA has prompted the search for IL-6-blocking agents as therapeutic options for this condition.

Rheumatoid arthritis (RA) is a serious, progressive disease characterized by chronic inflammation of synovial joints that frequently leads to functional disability.1 It is 2- to 3-times more prevalent in women than men and affects approximately 1% of the worldwide population.2

The pathophysiology of RA is complex and involves an interactive network of autoantibodies, T and B cells, cytokines, and other inflammatory mediators.1,3 IL-1 was the first cytokine isolated from the synovial fluid of RA patients4; since then, many other cytokines have been implicated in the pathogenesis of RA including tumor necrosis factor a (TNF-a) and a host of interleukins (ILs): IL-1a, IL-1b, IL-6, IL-7, IL-15, IL-17A, IL-17F, IL-18, IL-21, IL-23, IL-32, and IL-33.5

Targeting Inflammatory Cytokines in RA

A better understanding of the pathophysiology of RA has opened up new avenues for research focused on the inhibition of inflammatory cytokines as a therapeutic target for RA.  The result of a concerted research effort spanning the past 3 decades is a series of targeted biologic agents for RA, the first of which was a TNF antagonist — etanercept — approved in 1998 by the US Food and Drug Administration (FDA).6 Following suit were 4 other TNF antagonists: infliximab, adalimumab, certolizumab pegol, and golimumab, as well as an IL-1 receptor antagonist, anakinra.6,7

Before the introduction of effective biologics, treatments for RA largely relied on combinations of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids, and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, chloroxine, sulfasalazine, and gold.6,8 Methotrexate is the most widely used DMARD and has become a standard for comparison of emerging RA therapies due to its long-term use, effectiveness, and acceptable safety profile.6

Although DMARDs, and methotrexate specifically, are effective in reducing the symptoms of joint inflammation and inhibiting disease progression, a significant number of patients with RA cannot tolerate these treatments or do not respond to them.1 It is in this group of patients that novel biologics have made the greatest difference.  

In a recent overview of emerging RA therapies, authors Jeffrey R. Curtis, MD, MPH, and Jasvinder A. Singh, MD, MPH, wrote that “overall, biologics are highly effective in reducing RA symptoms, slowing disease progression, and improving indices of physical function and quality of life.”6 They further noted that “clinical responses are often rapid: most patients experience improvements within a few weeks of starting treatment.”6

IL-6 Signaling

IL-6 is a 26 kDa protein8 consisting of 184 amino acids.9 It is secreted by numerous cell types — T and B cells, fibroblasts, monocytes, neutrophils, and synoviocytes3 — and is known for its critical role in differentiation of T cells. Beyond the immune system, IL-6 is also involved in liver regeneration, metabolic control, and regulation of the nervous system.9

Due to its pleiotropic activity and complex biology, IL-6 has been implicated in the pathogenesis of a range of inflammatory diseases including RA, systemic juvenile idiopathic arthritis, and Castleman disease.10

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IL-6 binds to IL-6R, a type I transmembrane protein found on target cells including hepatocytes, leucocytes, monocytes/macrophages, and megakaryocytes.3 Signaling begins once the IL-6-IL-6R complex associates with gp130, a 130kD transmembrane protein, initiating dimerization.10 In a series of events that follow, phosphorylation of Janus kinases (JAKs) takes place,10 as well as recruitment of signal transducer and activator of transcription (STAT) factors that then stimulate transcription of target genes.11

Because IL-6R also occurs in a soluble form (sIL-6R), signaling can take place via 2 mechanisms: classical signal transduction via the membrane-bound IL-6R, or trans-signaling whereby IL-6 binds with circulating sIL-6R.3 The IL-6-sIL-6R complex is capable of stimulating target cells that do not express the membrane-bound IL-6R and cannot be stimulated by IL-6 alone.11

Researchers have established that IL-6 classic and trans-signaling have distinct roles in the body: regenerative and protective functions of IL-6 are facilitated by classic signaling, while trans-signaling is implicated in the proinflammatory activity of IL-6.12 The proinflammatory effects of IL-6 trans-signaling include inhibition of T-cell apoptosis, recruitment of mononuclear cells, and inhibition of regulatory T cell (TREG) differentiation.13