Interleukin-6 (IL-6) is a signaling molecule, or cytokine, that plays a broad role in the body’s communication networks. It acts as a messenger, facilitating interactions between various cells and influencing a wide array of biological processes.
Understanding Interleukin-6
IL-6 is a protein and a type of cytokine, functioning as a messenger within the immune system. It is generated by various cells, including immune cells like macrophages and T cells, and non-immune cells such as fibroblasts, endothelial cells, and adipocytes. Its production increases in response to infections, tissue injuries, and other inflammatory stimuli.
For IL-6 to exert its effects, it must bind to specific receptors on target cells. The IL-6 receptor complex involves two main components: the IL-6 receptor (IL-6R), which binds IL-6, and glycoprotein 130 (gp130), which transmits the signal into the cell. While IL-6R expression is limited to certain cell types like hepatocytes and specific leukocytes, gp130 is widely present across most tissues, allowing for broad cellular responses to IL-6.
There are two main ways IL-6 signals: classic signaling and trans-signaling. In classic signaling, IL-6 binds to the membrane-bound IL-6R on cells that express it, such as hepatocytes, leading to a response. Trans-signaling involves IL-6 binding to a soluble form of its receptor (sIL-6R), forming a complex that can then activate any cell expressing gp130, which is nearly ubiquitous.
Diverse Roles in the Body
IL-6 plays a diverse role in the body’s normal physiological processes, demonstrating both pro- and anti-inflammatory activities depending on the context. During an acute immune response, it mediates inflammation, stimulating the production of acute phase proteins like C-reactive protein and serum amyloid A by the liver. It also contributes to fever induction by affecting the hypothalamus and supports the growth and differentiation of immune cells, including B cells and T cells.
Beyond its immune functions, IL-6 is involved in metabolic regulation. It influences glucose and lipid metabolism, contributing to energy balance within the body. For instance, IL-6 can affect iron levels by inducing hepcidin production, which in turn reduces serum iron.
The molecule also contributes to tissue repair and regeneration. It promotes the differentiation or proliferation of various non-immune cells, aiding in healing and recovery. This includes its involvement in the differentiation of oligodendrocytes and the regeneration of peripheral nerves.
IL-6 influences the nervous system and brain function. It can act as a neurotrophic factor, supporting nerve cell health and development. It also influences mood and cognition, although excessive levels can be associated with neuropathological changes like those seen in multiple sclerosis, Parkinson’s, and Alzheimer’s disease.
When IL-6 Goes Wrong
While IL-6 is beneficial for health, its dysregulation can contribute to various diseases. Excessive or prolonged IL-6 activity is a factor in chronic inflammatory diseases. Unlike acute inflammation, which is a controlled response, chronic inflammation involves persistent IL-6 activity, often leading to tissue damage.
IL-6 plays a role in autoimmune diseases where the immune system mistakenly attacks the body’s own tissues. Conditions such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus are linked to elevated IL-6 levels. In these diseases, IL-6 can promote the differentiation of certain T cell subsets, leading to immune dysregulation.
The cytokine can also promote tumor growth, survival, and metastasis in various cancers. Elevated IL-6 levels are associated with a poorer prognosis in cancer patients. It can create a pro-tumor microenvironment, influencing interactions between the tumor and immune cells.
A severe consequence of IL-6 dysregulation is the “cytokine storm,” an uncontrolled inflammatory response. This exaggerated immune reaction, characterized by high levels of IL-6 and other cytokines, can occur in severe infections like COVID-19 or as a side effect of certain therapies such as CAR T-cell therapy. The cytokine storm can lead to widespread tissue damage and organ failure.
Modulating IL-6 for Health
Given its involvement in numerous diseases, targeting IL-6 or its signaling pathway has become a therapeutic strategy. The aim is to modulate its activity to reduce inflammation and disease progression without completely suppressing its beneficial functions.
One example of an IL-6 inhibitor is tocilizumab, a humanized monoclonal antibody. This medication works by selectively binding to the IL-6 receptor, preventing IL-6 from attaching and activating its signaling pathways. By blocking this interaction, tocilizumab helps to reduce the inflammatory response in conditions where IL-6 levels are excessively high.
Tocilizumab is approved for treating several inflammatory conditions, including rheumatoid arthritis, systemic juvenile idiopathic arthritis, and giant cell arteritis. It has also been used to manage cytokine release syndrome, a severe inflammatory response that can occur after certain immunotherapies. The use of such inhibitors demonstrates a targeted approach to managing diseases driven by IL-6 dysregulation.