How IL-6 Impacts Health and Disease

THE ROLE OF IL-6 IN HEALTH AND DISEASE VIDEO SERIES

Learn about the importance of interleukin-6, or IL-6, in this short, 4-part video series exploring the many roles of this multifunctional cytokine. Join us as we discuss the actions of IL-6 in health and homeostasis, as well as in the pathogenesis and progression of inflammatory diseases such as rheumatoid arthritis (RA).

IL-6 and Homeostasis

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In this video, we will discuss the importance of interleukin-6, or IL-6. IL-6 is a multifunctional signaling molecule known as a cytokine. In the healthy individual, IL-6 is critical for maintaining homeostasis in many organ systems.

In the immune system, IL-6 regulates T cell differentiation and neutrophil localization. IL-6 also has a central role in the brain, where it is involved in neuronal homeostasis and glial cell generation. In the cardiovascular system, IL-6 mediates vascular dilation, permeability, and growth through its actions on endothelial cells. And in adipose tissue, the liver, the pancreas, and the GI tract, IL-6 acts as an important metabolic regulator. Lastly, IL-6 plays a role in bone homeostasis, as it mediates bone metabolism and remodeling through its effects on osteoclasts.

This broad range of biological activity stems from the unique biology of IL-6, which is able to signal via at least two distinct mechanisms, called cis- and trans-signaling. Cis or “classical” signaling is mediated by the membrane-bound form of the IL-6 receptor, mIL-6R. In general, cis-signaling is important for homeostatic and protective functions of IL-6, and is normally predominant in the healthy individual. Trans- or “soluble” signaling, is mediated by the soluble form of the receptor, sIL-6R. Trans-signaling promotes the proinflammatory activity of IL-6, and is favored when IL-6 becomes dysregulated, such as during chronic inflammation.

During cellular activation, free IL-6 first binds to its receptor; this complex then associates with the cell surface glycoprotein gp130. The fully assembled complex initiates a signaling cascade through downstream pathways, such as JAK/STAT, MAP kinase, and PI3 kinase.

While cis-signaling is restricted to cells that express mIL-6R, trans-signaling is possible in all cells expressing the ubiquitous gp130, only some of which are shown here. Thus, these two signaling mechanisms allow virtually all cell types to respond to IL-6.

In summary, the cytokine IL-6 is critical for maintaining homeostasis in the healthy individual, and IL-6 signaling affects many different cell types through its unique dual signaling mechanism. Consequently, when IL-6 is dysregulated or chronically overproduced, a wide variety of organ systems can be impacted, which may lead to disruption of homeostasis in the essential biological processes we just discussed. This can lead to physiological consequences. Indeed, dysregulated IL-6 signaling can contribute to the initiation and pathogenesis of certain diseases, such as rheumatoid arthritis, or RA.

To find out more about IL-6, please tune in for upcoming videos in this series.

The cytokine interleukin-6, or IL-6, plays an important role in both health and disease, and has numerous roles in the inflammatory process. In our previous video, we discussed the role of IL-6 in homeostasis, and in this video, we will cover how the dysregulation of IL-6 can affect homeostasis and contribute to the development of disease.

Normally, serum concentrations of IL-6 are relatively low. However, during infection or injury, innate immune cells are activated and rapidly secrete large quantities of IL-6. This leads to drastic increases in the levels of circulating IL-6, which helps promote and coordinate the proinflammatory activities of cells throughout the body, thereby stimulating pathogen elimination and/or wound healing. These elevations of IL-6 are immediate, local, and temporary, and once the infection or trauma is resolved, circulating IL-6 is restored to basal levels.

While the activities of IL-6 have a protective role during acute inflammation, when IL-6 is persistently elevated or overproduced without returning to basal levels, it can contribute to the development of autoimmunity. This is because persistently elevated IL-6 signaling facilitates interactions between the innate and adaptive immune responses.

IL-6 secreted by innate cells promotes the differentiation of B cells into antibody-producing cells, and also regulates the balance between T helper 17 effector cells and regulatory T cells. When IL-6 is overproduced, the balance of T cells shifts to favor T helper 17 cells, which are believed to play an important role in the development of autoimmunity. This disrupts immune homeostasis and can contribute to the development of autoimmune diseases such as rheumatoid arthritis (RA).

In fact, IL-6 is one of the most abundant cytokines in the serum and joint fluid of patients with RA, helping drive disease pathogenesis. Serum levels of IL-6 have been found to be up to approximately 10 times higher in patients with RA compared to healthy controls, and correlate with index of disease activity. In the joint fluid, IL-6 levels have been observed to be as much as 100- to 1000-fold higher in patients with RA.

In summary, transient increases in IL-6 are protective during acute inflammation. However, persistent elevations in IL-6, such as is observed in RA, can contribute to chronic inflammation and autoimmunity.

To find out more about IL-6, please watch our previous video, “IL-6 and Homeostasis,” and tune in for upcoming videos in this series.

In our previous videos, we learned about the widespread biological effects of the cytokine interleukin-6, or IL-6, including numerous roles in the inflammatory process. In this installment, we will discuss how the activities of persistently elevated IL-6 can contribute to the progression of inflammatory diseases, such as rheumatoid arthritis, or RA.

At sites of acute inflammation in RA, innate immune cells and endothelial cells release IL-6, which can then interact with soluble IL-6 receptors released by incoming neutrophils to initiate trans-signaling in the local environment, including endothelial cells. These cells can then secrete factors that prompt inflammatory cells such as monocytes to infiltrate the joint synovium, contributing to the shift from acute to chronic inflammation.

In addition to promoting recruitment of inflammatory cells, IL-6 promotes osteoclast proliferation. IL-6 also induces proliferation of synoviocytes and the production of vascular endothelial growth factor, or VEGF. These activities lead to a thickening of the synovial tissue known as pannus. The pannus directly interfaces with joint cartilage and bone, causing cartilage degradation and bone erosion.

IL-6 further drives joint inflammation and destruction by stimulating the production of autoantibodies through its actions on B cells. Autoantibodies may be involved in articular and systemic bone loss through the promotion of osteoclast differentiation. Furthermore, continually produced IL-6 drives a positive feedback loop leading to even more IL-6 production, perpetuating the cycle of inflammation.

In summary, when persistently elevated in RA, IL-6 can promote chronic inflammation, pannus formation, autoantibody production, and cartilage degradation and bone erosion. The cumulative result of these actions of IL-6 is the progression of RA, a chronic, systemic, autoimmune disease, and levels of IL-6 have been found to correlate with disease activity and duration of RA.

To find out more about IL-6, watch our previous videos in this series, and tune in for our upcoming videos.

In our previous videos, we discussed the multifunctional signaling molecule interleukin-6, or IL-6, and its numerous roles in homeostasis and inflammation, as well as its role in the progression of rheumatoid arthritis, or RA. In this video, we will learn about the role of IL-6 in driving the articular and systemic manifestations of RA.

Within the joints of patients with RA, IL-6 levels are persistently elevated, perpetuating chronic synovitis and promoting joint damage through activation of pro-inflammatory cells and mediators, activation of cartilage-degrading cells and promotion of pannus formation, and stimulation of osteoclast activity, leading to bone erosion. In fact, the progression of joint damage in patients with RA has been found to correlate with the levels of IL-6 in their joints.

Chronically elevated IL-6 can also affect a broad range of tissues throughout the body, which may contribute to an array of systemic manifestations.

IL-6 stimulates the production of acute-phase proteins, including C-reactive protein (CRP), and can also contribute to vascular endothelial dysfunction, both of which have been linked to increased risk of cardiovascular disease in RA patients.

IL-6 also increases production of hepcidin, another acute-phase protein, which contributes to the development of anemia of chronic disease.

In adipose tissue, persistently elevated IL-6 can affect lipid metabolism and promote dyslipidemia.

In addition, through its effects on the hypothalamic-pituitary-adrenal (HPA) axis, dysregulated IL-6 can contribute to fatigue and mood disorders and can also contribute to systemic pain by interacting with neurons.

Lastly, the dysregulation of osteoclasts and osteoblasts by overexpressed IL-6 can contribute to the development of systemic osteoporosis, which has been linked to an increased risk of bone fracture.

In summary, chronic dysregulation of IL-6 has widespread effects in patients with RA, driving not only the physical manifestations observed in the joint, but also many of the systemic manifestations typically associated with RA.

To find out more about IL-6, please watch the other videos in this series.

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