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IL-6 and the Articular Manifestations of Rheumatoid Arthritis

IL-6 and the Articular Manifestations of Rheumatoid Arthritis

The Role of IL-6 Signaling in Rheumatoid Arthritis

Ernest Choy, MD:
The Dual Signaling Mechanism of IL-6 in RA   

Alvin F. Wells, MD, PhD:
The Contributions of IL-6 to Bone Resorption in RA

Rheumatoid arthritis, or RA, is a chronic systemic autoimmune disease driven by a complex network of cytokines and other immune processes.

Patients with RA commonly experience symptoms both at the joint and beyond. Within the joint, pain and stiffness are common.1,3-7 Interleukin-6, or IL-6, is one of the most abundant cytokines in the serum and synovial fluid of the inflamed joints of patients with RA and isassociated with disease activity and articular destruction.

During active disease, there is a marked increase in proliferation or hyperplasia, of cells of the synovial lining within the joint. The pannus degrades cartilage and invades bone, causing further joint damage.

In RA, elevated IL-6 perpetuates chronic synovitis in multiple ways.

IL-6 activates pro-inflammatory cells and mediators within the joints, including, but not limited to, neutrophils, macrophages, T cells, B cells, and fibroblast-like synoviocytes, which are also called FLS cells.

IL-6 regulates B cell differentiation and autoantibody production.

IL-6 stimulates plasmablasts to differentiate into mature plasma cells.

In addition, IL-6 increases the CD4+ T cell production of IL-21, which promotes CD4+ T-cell–mediated B cell activation and stimulates antibody production.

IL-6, by inducing C-reactive protein, or CRP, activates the complement system to target healthy tissue.

Abundant, activated complement is found in the synovial fluid of patients with RA.

Complement, in conjunction with autoantibody immune complexes, places a target on healthy tissues for destruction.

FLS cells play a key role in chronic inflammation and joint destruction in RA.

FLS cells both produce IL-6 and are activated by IL-6, increasing their proliferation.

FLS cells also promote inflammatory cell recruitment and activation, as well as angiogenesis, through the expression of immunomodulating cytokines and mediators, including IL-6.

IL-6 increases levels of vascular endothelial growth factor, also known as VEGF, synergistically with other pro-inflammatory cytokines. VEGF is central to the formation and maintenance of the pannus through stimulation of angiogenesis.

The invasive properties of FLS cells have been shown to correlate with radiographic and histological damage in RA.

The combined presence of IL-6 and TGF-beta stimulates naïve T cells to differentiate into Th17 cells.

Th17 cells in turn release more IL-6, which further promotes Th17 differentiation.

Additionally, Th17 cells produce IL-17, which also contributes to RA pathogenesis in part by increasing RANKL expression on osteoblasts.

IL-17 activates synoviocytes to induce the production of IL-6, setting up a positive feedback loop of IL-6 expression.

FLS cells are the main effector cells of cartilage breakdown, releasing large amounts of matrix metalloproteinases, or MMPs, which cause a characteristic rapid loss of the cartilage matrix.

FLS cells also contribute to bone erosion through secretion of factors that promote osteoclast differentiation, survival, and activity.

IL-6 stimulates osteoclastogenesis and osteoclast activity, contributing to structural damage through bone resorption.

Persistently elevated IL-6 may play a central role in the articular manifestations of RA, resulting in pain and disability in patients.

Rheumatoid arthritis, or RA, is a chronic systemic autoimmune disease driven by a complex network of cytokines and other immune processes.

Patients with RA commonly experience symptoms both at the joint and beyond. Within the joint, pain and stiffness are common.1,3-7 Interleukin-6, or IL-6, is one of the most abundant cytokines in the serum and synovial fluid of the inflamed joints of patients with RA and isassociated with disease activity and articular destruction.

During active disease, there is a marked increase in proliferation or hyperplasia, of cells of the synovial lining within the joint. The pannus degrades cartilage and invades bone, causing further joint damage.

In RA, elevated IL-6 perpetuates chronic synovitis in multiple ways.

IL-6 activates pro-inflammatory cells and mediators within the joints, including, but not limited to, neutrophils, macrophages, T cells, B cells, and fibroblast-like synoviocytes, which are also called FLS cells.

IL-6 regulates B cell differentiation and autoantibody production.

IL-6 stimulates plasmablasts to differentiate into mature plasma cells.

In addition, IL-6 increases the CD4+ T cell production of IL-21, which promotes CD4+ T-cell–mediated B cell activation and stimulates antibody production.

IL-6, by inducing C-reactive protein, or CRP, activates the complement system to target healthy tissue.

Abundant, activated complement is found in the synovial fluid of patients with RA.

Complement, in conjunction with autoantibody immune complexes, places a target on healthy tissues for destruction.

FLS cells play a key role in chronic inflammation and joint destruction in RA.

FLS cells both produce IL-6 and are activated by IL-6, increasing their proliferation.

FLS cells also promote inflammatory cell recruitment and activation, as well as angiogenesis, through the expression of immunomodulating cytokines and mediators, including IL-6.

IL-6 increases levels of vascular endothelial growth factor, also known as VEGF, synergistically with other pro-inflammatory cytokines. VEGF is central to the formation and maintenance of the pannus through stimulation of angiogenesis.

The invasive properties of FLS cells have been shown to correlate with radiographic and histological damage in RA.

The combined presence of IL-6 and TGF-beta stimulates naïve T cells to differentiate into Th17 cells.

Th17 cells in turn release more IL-6, which further promotes Th17 differentiation.

Additionally, Th17 cells produce IL-17, which also contributes to RA pathogenesis in part by increasing RANKL expression on osteoblasts.

IL-17 activates synoviocytes to induce the production of IL-6, setting up a positive feedback loop of IL-6 expression.

FLS cells are the main effector cells of cartilage breakdown, releasing large amounts of matrix metalloproteinases, or MMPs, which cause a characteristic rapid loss of the cartilage matrix.

FLS cells also contribute to bone erosion through secretion of factors that promote osteoclast differentiation, survival, and activity.

IL-6 stimulates osteoclastogenesis and osteoclast activity, contributing to structural damage through bone resorption.

Persistently elevated IL-6 may play a central role in the articular manifestations of RA, resulting in pain and disability in patients.

Interleukin-6, also known as IL-6, is a multifunctional cytokine that is involved in both articular and systemic manifestations of rheumatoid arthritis, or RA.

IL-6 can signal through membrane-bound receptors in a process called classical or cis-signaling and also through soluble receptors in a process called trans-signaling.

This dual signaling mechanism allows IL-6 to interact with a wide range of cells.

IL-6 released at sites of inflammation diffuses into circulation, enabling it to exert widespread effects.

In cis-signaling, IL-6 binds to its membrane-bound receptor, which is mainly expressed in hepatocytes and white blood cells, including some types of T cells, monocytes, macrophages, activated B cells, and neutrophils.

This complex then associates with signal-transducing glycoprotein 130, or gp130, a membrane protein expressed in all tissues.

In RA, one example of IL-6 cis-signaling is the activation of hepatocytes, which in turn contributes to the induction of C-reactive protein, or CRP, an acute-phase protein produced in the liver and associated with inflammation and disease activity in RA.

IL-6 trans-signaling contributes to RA joint damage.

In trans-signaling, IL-6 binds to its soluble receptor, which is present in serum and synovial fluid.

Fibroblast-like synoviocytes, or FLS cells, present within the joint do not contain membrane-bound receptors, yet are highly responsive to IL-6 via trans-signaling and play a key role in chronic inflammation and joint destruction in RA.

Whether IL-6 binds to its membrane-bound or soluble receptor, it is the subsequent association with gp130 that initiates the signaling cascade.

This cascade includes activation of the Janus kinasesignal transducer and activator of transcription, or JAK-STAT, pathway and the mitogen-activated protein kinase, or MAPK, pathway.

In the joint, activation of these pathways induces the production of matrix metalloproteinase, or MMP, which contributes to cartilage degradation, and receptor activator of nuclear factor kappa-beta ligand, or RANKL, which contributes to bone resorption.

Both are characteristic of the structural damage associated with RA.

Through its dual signaling mechanism, IL-6 has widespread effects throughout the body, and elevated IL-6 signaling in RA may lead to the disruption of homeostasis in many cell types and physiologic processes.

Interleukin-6 is one of the cytokines in the body and is responsible for coordinating the body’s immune response when it encounters either an infection or chronic inflammation.

In patients with active rheumatoid arthritis we find elevated levels of interleukin-6 and the level of interleukin-6 in the blood correlated with disease activity.

IL-6 and its family of cytokines utilize a unique signaling pathway, which is different from many other cytokines. So cytokines usually binds to cell surface cytokine receptor and that causes cells to become activated.

In the case of IL-6, IL-6 will bind to cell surface IL-6 receptor, but this interaction on its own is in fact insufficient to cause cell activation. The complex must then bind to a second molecule on the surface of the cell called gp130 to cause the cells to become activated. This signaling pathway is called classical signaling.

In addition to this classical signaling pathway, IL-6 also has another signaling pathway called the trans-signaling pathway.

Many cytokine receptors are cleaved off by metalloproteinases to form soluble cytokine receptors. For many of these soluble cytokine receptors they are natural antagonists to the cytokine. So soluble TNF will compete with membrane-bound TNF receptor to bind to TNF as a way of neutralizing the effect of the cytokine. Now in the case of IL-6, soluble IL-6 receptor are not antagonists to IL-6. In fact, soluble IL-6 receptor is able to bind to any circulating IL-6 and this complex is then able to stimulate any cells that express gp130 to cause the cell to become activated. So soluble IL-6 receptor is in fact pro-inflammatory rather than anti-inflammatory and this unique signaling pathway is known as trans-signaling.

When IL-6, IL-6 receptor, and gp130 complex together it will start a series of intracellular signaling pathway, mainly driven by the JAK kinase systems. When the JAK kinase become activated it also leads to the activation of transcriptional factors, especially STAT1 and STAT3 and that amplifies the inflammatory cascade.

IL-6 receptor is only expressed by the hematopoietic cells as well as the hepatocytes. So in terms of IL-6 classical signaling, these are the cells that tend to be responsive to IL-6 on its own. But in terms of IL-6 trans-signaling, almost all cells in the body express gp130 and therefore are able to respond to IL-6 trans-signaling.

In normal individuals there’s a low level of IL-6 and soluble IL-6 receptor, which allows a small degree of trans-signaling to occur, but this is tightly controlled because there are soluble gp130 in the circulation too, which can inhibit the trans-signaling process. But the soluble gp130 level is steady in individuals. So even if the patient develop rheumatoid arthritis and have active inflammation, soluble gp130 level do not become increased and therefore the trans-signaling overcome the blockade put in place by soluble gp130 and cause inflammation in the systemic circulation.

In normal individuals, there is a low level of IL-6 as well as soluble IL-6 receptor in the circulation as a way of maintaining normal physiology. In patients with rheumatoid arthritis, especially those with active disease, the level of IL-6 increase up to 100 fold higher.

In addition if we measure samples in the synovial fluid and the blood we find elevated level in the synovial fluid, showing that IL-6 is produced in the inflamed joint and then leak out into the systemic circulation. When it leaks out to the systemic circulation it’s responsible for driving inflammation we observe in patients with rheumatoid arthritis.

Under normal conditions, bone remodeling’s a dynamic process. I like to make the analogy of a yin and a yang. You have two different types of cells. The first type, osteoblast, and a simple way to remember that: the B stands for bone forming. And then you have the osteoclasts. The C stands for bone chewing.

So the osteoclasts, they break down the bone, kind of make like a little cavity and the osteoblasts come back like the little men laying down cement to allow the bones to kind of fill in. They key thing to remember that with bone remodeling, it starts at birth and goes all the way to our end of our life.

If you do an x-ray of the hand or the knee, at the tips of the bone we look for what's called periarticular osteopenia. Simply put that means that at the tips of these areas we see there's less matrix development of the bone and that could lead to weakening and thinning of the bone. Second we see that in the areas where there's soft tissue that abuts to bone, where the capsule and synovium comes off, that can lead to inflammation, a pannus formation that can lead to the erosions that we all see on the x-rays.

All patients with rheumatoid arthritis are at an increased risk of getting systemic bone loss from osteoporosis.

Not in the joints where there's only erosions and inflammation, but systemic osteoporosis.

Patients with rheumatoid arthritis have the presence of what we call autoantibodies. These include rheumatoid factor but also the anti-citrullinated peptide antibodies, the so called ACPA.

Data has shown that these autoantibodies can directly bind to osteoclasts and that interaction of the autoantibodies on the surface of the osteoclasts can stimulate those cells. Once stimulated the osteoclasts lead to the production of enzymes and other molecules that break down the bone.

Studies have shown that patients with ACPA can have the presence of these autoantibodies in their serum before they develop clinical symptoms of rheumatoid arthritis. Other studies have shown that patients who have positive ACPA are at an increased risk for developing bone loss. The take home message is that whether somebody has rheumatoid factor or ACPA positivity, they're at increased risk for developing bone loss.

As a rheumatologist and an immunologist, I know that cytokines play an important role in bone remodeling in patients with rheumatoid arthritis.

We know that specific cytokines, whether interleukin-1, interleukin-6, or tumor necrosis factor, may play a role in how the osteoclasts and the osteoblasts interact in the specific joints. Whether the hand, the knee, or the foot in patients with rheumatoid arthritis.

One of the mechanisms by which IL-6 contributes to the bone loss in patients with rheumatoid arthritis is via the direct stimulation of osteoclasts. Studies have shown that interleukin-6 is one of the most abundant cytokines in the synovium, and in the serum of patients with rheumatoid arthritis.

IL-6 together with other molecules such as the receptor activator of nuclear factor-B, the so called RANK molecule, interaction with the RANK ligand on the surface of osteoclast can lead to the upregulation of these cells, and once upregulated, these osteoclasts can lead to the breakdown of bone.

Recent studies show that the acute phase reactant, the C-reactive protein, can actually contribute to bone loss in patients with rheumatoid arthritis. The acute phase reactant comes from the liver, and the liver has been stimulated by interleukin-6 in many patients with active disease. The take home message here is that patients with high levels of C-reactive protein can lead to significant bone loss and significant clinical activity in patients with rheumatoid arthritis.

Another name for interleukin-6 is called the B-cell stimulating factor. We know that interleukin-6 can play a significant role in the B cell differentiation. Under the influence of interleukin-6, B cells can lead to an up regulation, essentially increase the division of those cells and that leads to the production of autoantibodies. That's important for a patient with rheumatoid arthritis because in the presence of IL-6, patients can develop rheumatoid factor and the so called ACPA antibodies and these can correlate with significant clinical symptoms in patients with active rheumatoid arthritis.

Recent studies have revealed that in patients with rheumatoid arthritis, there are high levels of interleukin-6 both in the serum and in the synovial fluid.

The take-home message here is that the presence of high levels of IL-6 in patients with active rheumatoid arthritis can correlate with significant structural damage in rheumatoid arthritis.

The Role of IL-6 in Rheumatoid Arthritis: Expert Perspectives

A podcast series brought to you by Sanofi Genzyme and Regeneron

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Beyond the joints: systemic manifestations of IL-6 elevation in rheumatoid arthritis
by Dr Grace Wright
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Dual signaling: the driver behind the pleiotropic nature of IL-6
by Dr Alan Epstein