Interleukin-6 (IL-6) is a multifunctional cytokine with a wide range of immune activities and a strong ability to trigger the acute phase response in host defense. Overexpression of this cytokine has been implicated in the pathology of a number of diseases including diabetes, rheumatoid arthritis and cancer.
.jpg "interleukin 6")
Image Credit: Jarun Ontakrai/Shutterstock.com
IL-6 in inflammatory disease
The systemic response to severe infection is characterized by fever, leukocytosis and changes in the liver’s production of various proteins. IL-6 is one of the key proinflammatory cytokines in triggering this response and is almost entirely responsible for inducing fever and the acute phase response in the liver. In life-threatening infections, the IL-6 level is elevated and correlates with the severity of sepsis and death rate. IL-6 levels are also raised in almost all diseases that involve chronic inflammation such as diabetes and rheumatoid arthritis.
IL-6 and diabetes
Inflammation has long been associated with diabetes and obesity, although it remains unclear how the proinflammatory state emerges. Along with other proinflammatory cytokines, IL-6 is elevated in patients with obesity and insulin resistance.
Research has shown that one of the key regulators of the inflammatory response called NF-kappaB (NF-kB) is activated in the liver and adipose tissue of mice that have obesity and insulin resistance. These mice also have high levels of IL-6. The upstream kinase required for NF-kB activation is IKKb (I kappa B kinase beta) and targeted deletion of IKKb in myeloid cells results in decreased levels of immune resistance and IL-6 among mice that are fed high-fat diets.
The wild type mice go on to develop increased insulin resistance when fed high-fat diets. This suggests that activation of NF-kB through IKKb may be the pathway by which IL-6 and other inflammatory cytokines are upregulated in diabetes and other inflammatory conditions.
Obesity may stimulate inflammation through oxidative stress as a result of high concentrations of free fatty acids. NF-kB is activated in tissue macrophages and circulating monocytes and inflammatory cytokines such as IL-6 are released, which results in a cycle of inflammation, raised insulin resistance and further oxidative stress.
IL-6 and rheumatoid arthritis
IL-6 is a key effector in the joint damage caused by inflammation in rheumatoid arthritis. The trigger of RA in this disease remains unclear, but cytokines including IL-6 are present at high concentrations in the arthritic joints, blood and synovium of people with this disease.
Studies have also shown that mice genetically engineered to be deficient in IL-6 do not develop collagen-induced arthritis. Although the exact cause of RA is not fully understood, researchers suspect that the initial events that lead up to chronic inflammation and joint damage involve the innate immune response. NF-kB is also activated in the synovia of patients with rheumatoid arthritis, which would explain the increased concentration of IL-6 observed in this disease.
IL-6 and cancer
In chronic inflammation, inflammatory cells move towards a site where they expand, differentiate and then fail to die because apoptosis is dysregulated. NF-kB is a key regulator of these effects. For neoplasia to arise, several elements are required, including a self-sufficiency in growth signals, a non-responsiveness to signals that inhibit growth, the ability to avoid apoptosis, unrestricted ability to proliferate, the ability to invade tissue and spread and ongoing angiogenesis.
The majority of these elements are present as the result of NF-kB activation. As a growth signal, IL-6 can block apoptosis and as such, is an effector signal of activated NF-kB in the emergence of neoplasia.
One example of a cancer where IL-6 plays a key role is multiple myeloma, where the terminal differentiation of plasma cells is dependent on IL-6. Originally, researchers believed that multiple myeloma cells produce IL-6 independently, but later studies have shown that the main source of IL-6 in this cancer is the bone marrow stroma.
References
Further Reading
Study reveals inflammation's role in long COVID's lingering effects