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Elevated IL-6 signaling and its potential correlation with systemic manifestations of rheumatoid arthritis


IL-6 is one of the most abundant cytokines in the serum and synovial fluid of patients with rheumatoid arthritis ( RA ).
In rheumatoid arthritis, IL-6 is synthesized and secreted by cells of the synovia of inflamed joints including FLS, monocytes / macrophages, and neutrophils.
IL-6 originating from articular sources can then diffuse into circulation and affect a broad range of distal cells / tissues due to its dual signaling mechanism.

Increased IL-6 levels may be associated with systemic manifestations of rheumatoid arthritis.

Induction of acute-phase proteins

A) C-reactive protein - IL-6 signaling is a major contributor to induction of C-reactive protein ( CRP ) and other acute-phase proteins.

The acute-phase response is the change in the concentration of certain plasma proteins, such as CRP, hepcidin, and serum amyloid A, which are produced by the liver in response to infection, tissue injury, neoplastic growth, or immunological disorder.

IL-6 is a major inducer of acute phase protein levels, although other cytokines such as IL-1, TNF-alpha, TGF-beta1, and IFN-gamma also have stimulatory effects.

Peak values of CRP usually occur within 24 to 72 hours after experimental induction with IL-6 and last for several days, although circulating levels remain elevated in cases of chronic inflammation.

A prospective study found that an elevated baseline CRP level was a significant predictive factor for radiographic damage at 3 years in patients with rheumatoid arthritis.

Several studies investigating the relationship between CRP levels and cardiovascular disease have found that CRP is associated with an increased risk of myocardial infarction, stroke, sudden death from cardiac causes, and peripheral arterial disease.

Patients with rheumatoid arthritis are at higher risk for cardiovascular illness ( standardized mortality rate, approximately 1.5 ) which includes myocardial infarction, cerebrovascular events, and heart failure.

Data suggest that CRP levels are a strong predictor of cardiovascular events, as evidenced by improved clinical outcomes in a general patient population with lowered CRP levels following statin therapy compared to those with higher CRP levels, regardless of the resultant level of low-density lipoprotein ( LDL ) cholesterol.

B) Hepcidin - Elevated IL-6 signaling may lead to hypoferremia through induction of hepcidin

IL-6 increases production of hepcidin, an acute-phase protein that is a key regulator of iron homeostasis with antimicrobial properties.

In a study of six healthy human volunteers infused with IL-6, urinary hepcidin levels rose 7.5-fold within 2 hours.
IL-6 induces hepcidin expression in the liver via the JAK-STAT signaling pathway.

Hepcidin reduces iron bioavailability, which is critical for new hemoglobin synthesis, by inhibiting iron uptake in the duodenum and iron release from macrophages in the spleen and elsewhere.

As a result, when hepcidin levels are increased, concentrations of iron in the blood are limited, a condition referred to as hypoferremia.

Effects of persistent elevated hepcidin levels in RA and the prevalence of anemia, sleep disturbances, and fatigue

Hepcidin is a potential contributing cause of anemia in patients with chronic inflammatory disease.
Anemia is one of the most frequent systemic manifestations of rheumatoid arthritis, occurring in approximately one-third of patients, and has been associated with more severe joint disease.
In addition, anemic patients with rheumatoid arthritis tend to have greater radiographic progression than non-anemic patients.
In humans, serum hepcidin levels have been shown to be highest in patients with rheumatoid arthritis and anemia, whereas healthy adults have been reported to have the lowest levels.

Baseline hepcidin levels also correlated with CRP levels.

Anemia is a common contributor to fatigue. 40% to 80% of rheumatoid arthritis patients report fatigue as their most disabling symptom.
In addition to its role in hepcidin production, IL-6 has also been associated with other causes of fatigue.
IL-6–induced effects have been linked to functions of the HPA ( hypothalamic-pituitary-adrenal ) axis, including fatigue, and elevated levels of IL-6 have been positively correlated with fatigue in rheumatoid arthritis.

Studies have also shown that circulating levels of IL-6 may contribute to sleep disturbances in several different patient populations.

Contributing effects of elevated IL-6 signaling on energy homeostasis in rheumatoid arthritis

IL-6 functions as an energy sensor.
Prolonged myocyte activation during sustained exercise depletes glycogen stores, thus triggering a cascade of compensatory responses.
Glycogen depletion induces myocytes to produce and secrete IL-6 into plasma.

Following exercise, plasma IL-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent.

Circulating IL-6 promotes the conversion of hepatic glycogen into glucose, and subsequent glucose uptake and utilization by skeletal muscle.

In contrast, TNF-alpha levels are not increased by myocytes in response to sustained exercise.

In the context of muscle tissue, IL-6 also stimulates the production of anti-inflammatory cytokines and actually suppresses TNF-alpha production, which suggests IL-6 offers protection against TNF-induced insulin resistance.

A study has also suggested that IL-6 may have a beneficial role in the prevention of obesity-associated insulin resistance through a polarization of macrophages from a pro-inflammatory to an anti-inflammatory phenotype.

IL-6 plays important roles in the endocrine functions of pancreatic islet cells, specifically alpha and beta cells.

The IL-6 receptor is expressed by alpha cells, and IL-6 treatment of alpha cells promotes their proliferation and acutely regulates pro-glucagon gene expression and glucagon secretion.

Beta cells are a source of IL-6, and experimental models have shown that IL-6 protects the beta-cell population from TNF-alpha- and IFN-gamma–induced apoptosis, and preserves insulin secretory functions.

Adipose tissue stores triglycerides and is an active endocrine organ with a central role in maintaining normal energy homeostasis.
Adipocytes communicate with other cells involved in energy homeostasis through release of adipokines ( cytokines secreted by adipose tissue ) such as leptin and adiponectin.

IL-6 also functions as an adipokine; it can increase adipose cell size, and modulate leptin production and lipid metabolism.

The persistently elevated levels of circulating cytokines such as IL-6 in rheumatoid arthritis could be one of the contributing factors to muscle and adipose tissues becoming insulin-resistant during chronic inflammation, a condition referred to as an inflammatory metabolic state.

In addition, the biochemical composition of lipids is altered in response to chronic inflammation.
Rheumatoid arthritis is associated with reduced serum levels of total, high-density lipoprotein ( HDL ), and low-density lipoprotein ( LDL ), cholesterol.

Although effective therapies raise HDL, LDL, and total cholesterol levels as a consequence of reducing inflammation, these therapies also reduce the risk of cardiovascular events in patients with rheumatoid arthritis.

Circulating levels of IL-6 are elevated in some insulin-resistant states such as obesity.
Higher inflammatory activity and a reduced functional activity are associated with obesity in patients with rheumatoid arthritis.
Growing evidence suggests that IL-6 is not only produced by adipocytes but is also capable of inducing insulin resistance in these cells.

Effects of elevated IL-6 signaling on bone metabolism in rheumatoid arthritis

Rheumatoid arthritis leads to increased bone destruction, which places patients at risk for fractures.
In the clinical evaluation of synovial fluid from patients with rheumatoid arthritis, it was determined that the ratio of RANKL to osteoprotegerin ( OPG ), a protein that binds directly to RANKL and inhibits it from interacting with its receptor, reflects osteoclast function, and a higher ratio of RANKL to OPG is correlated to osteoclast hyperactivity and bone resorption in joints in patients with rheumatoid arthritis.

Similar to more general cases of inflammation, IL-6 can affect the RANKL/OPG ratio through two mechanisms during RA inflammation.
First, IL-6 directly stimulates osteoblasts to increase expression of RANKL, which can be bound by osteoclasts and drive their activation.
Second, IL-6 directly stimulates Th17 cells, which produce IL-17; IL-17 levels are significantly higher in the synovial fluid of patients with rheumatoid arthritis.
IL-6 induces macrophages / monocytes to produce IL-1 and TNF-alpha. IL-17, IL-1, and TNF-alpha all stimulate effector T-cell proliferation and activation, which contribute to tissue damage in patients with rheumatoid arthritis.
These newly formed, activated T cells can express RANKL.
Therefore, the increased number of T cells expressing RANKL increases the ratio of RANKL to OPG and thereby enhances osteoclast function.
The increased osteoclast function shifts the balance of bone resorption / formation toward resorption, resulting in reduced bone mineral density in patients with rheumatoid arthritis.

Elevated IL-6 signaling also inhibits bone regeneration by affecting osteogenesis.
The increased bone resorption activity associated with rheumatoid arthritis translates to articular bone damage and systemic bone loss.

Elevated IL-6 levels are associated with generalized bone mineral density loss, a common systemic manifestation of rheumatoid arthritis

The prevalence of bone mineral density loss in the overall RA patient population has been reported as between 20% and 56%.

The disruption of homeostasis caused by elevated IL-6 signaling, and the resultant increase in bone resorption, can lead to overall bone mineral density loss, bone weakening, cartilage destruction, and an increased susceptibility to fracture.

Bone mineral density loss is especially prevalent in postmenopausal women with rheumatoid arthritis; generalized bone mineral density loss occurs in more than 50% of this population compared with approximately 15% in postmenopausal women without rheumatoid arthritis.

Studies have shown that estrogen blocks the synthesis of IL-6 by bone-forming osteoblasts and may also interfere with expression of IL-6 receptors.

Elevated serum levels of IL-6 and sIL-6R have also been associated with bone mineral density loss in postmenopausal women with rheumatoid arthritis, independent of glucocorticoid use.
Elevated serum levels of sIL-6R have also been shown to be the main predictor of bone mineral density loss in a study of postmenopausal women with rheumatoid arthritis, independent of well-known risk factors of generalized bone loss such as age, disease duration, low body mass index, and cumulative glucocorticoid dose.

Source: Leonard H. Calabrese, Ernest Choy, The contributions of IL-6 to disease manifestations of rheumatoid arthritis, 2015

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