Unveiling the Significance of Interleukin-6 (IL-6) in Health and Disease

Function Introduction of IL-6

Interleukin-6 (IL-6), a versatile cytokine, plays a pivotal role in immune regulation, inflammatory responses, as well as cell proliferation and differentiation. Produced by a range of cell types including T cells, B cells, macrophages, and fibroblasts, IL-6 exhibits a spectrum of functions critical to maintaining physiological equilibrium.

Firstly, IL-6 assumes a central role in immune regulation. It fosters the activation, proliferation, and differentiation of immune cells such as T and B cells, thus fortifying the immune response. IL-6 also spurs antibody production, a vital defense mechanism against infections. Moreover, IL-6 contributes to immune homeostasis, ensuring the seamless operation of the immune system.

Secondly, IL-6 is a key player in the inflammatory response. In instances of tissue infection, injury, or stimulation, IL-6 production escalates, orchestrating an inflammatory reaction. It triggers the migration of white blood cells and promotes tissue inflammation, facilitating the removal of pathogens and facilitating wound healing.

Lastly, IL-6 plays a pivotal role in cell proliferation and differentiation. It fuels the expansion and specialization of hematopoietic stem cells, leading to the generation of diverse blood cell types including red blood cells, white blood cells, and platelets. Additionally, IL-6 fosters cell growth and repair within tissues like the liver and kidney.

Nevertheless, the overactivity of IL-6 under certain conditions can contribute to diseases. Inflammatory diseases, autoimmune disorders, and specific tumors can arise due to the excessive production of IL-6, leading to abnormal inflammation, immune system disruptions, and unchecked cell proliferation.

Given its multifarious biological functions, IL-6 has become a significant focus of drug development. Notably, antibody drugs like anti-IL-6 receptor antibodies and anti-IL-6 antibodies have been engineered to combat inflammatory conditions and autoimmune diseases. The comprehensive understanding of IL-6's intricate functions and regulatory mechanisms holds considerable clinical and research importance, enhancing insights into its roles within diseases and therapeutic strategies.

IL6 Family

IL-6 family (IL-6 family) is an important cytokine family, which includes members such as IL-6, IL-11, IL-27, IL-31, LIF and CNTF. Members of the IL-6 family play key roles in physiological processes such as immune regulation, inflammatory response, and cell proliferation and differentiation.

In the 1970s, IL-6 was first identified by Kishimoto's group as a soluble protein produced by T cells that can activate B cells to differentiate into antibody-producing cells. Therefore, it was originally called B cell stimulating factor 2 (BSF-2) .

In 1986, researchers discovered IFN-β2 and a 26-kD protein in fibroblasts that were shown to be identical to BSF-2. In the same year, the cDNA of human BSF-2 gene was successfully cloned.

In 1987, hepatocyte-stimulating factor and plasmacytoma growth factor were cloned, which were also shown to be IL-6, and multiple biological activities of the protein were confirmed.

The molecule was first named IL-6 in 1988 at a conference entitled "Acute Phase and Regulation of the Immune Response: A Novel Cytokine" .

Fig.1 Cytokine receptor usage by the IL-6 family of cytokines.[25]

IL-6 Signaling Pathway

Classic Signaling

Classic IL-6 signaling is mediated strictly through membrane-bound receptors, IL-6Rα and gp130[7]. IL-6 first binds to IL-6Rα on the cell surface which creates a high affinity for transmembrane gp130. Two trimeric receptor complexes (IL-6/IL-6Rα/gp130) homodimerize; IL-6 of one trimeric complex binds to the D1 domain of gp130 of the second trimeric complex, forming a signal transducing hexameric receptor complex[8]. The IL-6/IL-6Rα/gp130 receptor complex activates mitogen activated protein kinase (MAPK), phosphatidylinositide-3-kinase (PI3K), Janus kinases (JAKs), and signal transducer and activator of transcription (STATs) signaling cascades. Formation of the IL-6/IL-6Rα/gp130 hexameric complex recruits the JAK family of non-receptor tyrosine kinases (JAK1, JAK2, and TYK2) to the membrane which associate with and phosphorylate the cytoplasmic tail of gp130 at five tyrosine residues (Y759, Y767, Y814, Y905, and Y915)[9]. Phosphorylated gp130 serves as a docking site for STAT1 and STAT3 transcription factors that are subsequently phosphorylated by JAKs at Y701 and Y705, respectively[10-11]. Notably, IL-6 activates STAT3 more potently when compared to STAT1[12]. Upon phosphorylation, STAT3 undergoes a conformational change, detaches from the receptor complex, and homodimerizes allowing for STAT3 translocation into the nucleus to promote transcriptional activation[13]. STAT3 is negatively regulated by tyrosine phosphatases, disruption of JAKs and/or cytokine receptors by suppressors of cytokine signaling (SOCS), or direct protein inhibitors of activated STATs (PIAS)[14-16]. Receptor availability can also become a limiting factor for IL-6 signaling since IL-6 must be complexed with IL-6Rα in order to bind to gp130 receptor for signal transduction. Interestingly, transmembrane gp130 expression is ubiquitously expressed on most cell types; however, expression of membrane-bound IL-6Rα is restricted, therefore, limiting classic signaling to a small subset of cells[17-18]. Since IL-6 modulates pleiotropic effects beyond immune cells, it quickly became evident that IL-6 signals via alternative mechanisms outside of membrane-bound receptors, termed trans-signaling.

Trans-Signaling

IL-6 trans-signaling is mediated through a soluble form of IL-6Rα (sIL-6Rα) to potentiate IL-6 signaling in cells lacking sufficient expression of membrane-bound IL-6Rα. Originally detected in serum and urine samples, sIL-6Rα functions as an agonist for IL-6 signaling. sIL-6Rα is produced either by proteolytic cleavage of the membrane-bound IL-6Rα or alternative splicing of pre-mRNA[19-20]. Membrane-bound IL-6Rα undergoes proteolysis, or shedding, by disintegrin and metalloproteinase domain-containing proteins ADAM10 or ADAM17 to form sIL-6Rα[21-22]. Secreted IL-6 binds to sIL-6Rα which binds transmembrane gp130. Subsequently, two trimeric receptor complexes homodimerize to activate downstream signaling. Interestingly, gp130 can also present in a soluble form (sgp130) and sequesters IL-6/sIL6Rα, thus antagonizing IL-6 trans-signaling without impacting IL-6 classic signaling. However, sgp130 levels are almost negligible when compared to sIL-6Rα. Trans-signaling regulates the IL-6 immune response and mediates pro-inflammatory responses through recruitment of mononuclear cells, stimulation of endothelial cells, T-cell survival, and inhibition of regulatory T-cell differentiation[23]. Administration of IL-6 and sIL-6Rα activates STAT3 in endothelial cells, solely expressing membrane-bound gp130, to recruit leukocytes for local inflammation in vitro and in vivo. Since trans-signaling mediates the pro-inflammatory responses induced by IL-6, trans-signaling is referred to as the primary mechanism by which IL-6 signaling promotes tumorigenesis in multiple cancers[24]. In cancer, IL-6 trans-signaling induces therapeutic resistance, angiogenesis, and is associated with poor clinical outcome.

Fig.1 Interleukin-6 Classical and Trans-Signaling.[26]

Diseases Mediated by IL-6 and Its Clinical Significance

Interleukin 6 (IL-6) assumes a pivotal role in immune regulation, inflammatory responses, and cell proliferation, thereby profoundly impacting the development and treatment of a range of diseases. Here are several diseases mediated by IL-6 and their clinical significance:

1. Inflammatory Diseases: IL-6 emerges as a significant inflammatory mediator closely tied to conditions like rheumatoid arthritis and inflammatory bowel disease. Elevated IL-6 levels stimulate the migration and activation of inflammatory cells, intensifying the inflammatory response and leading to tissue damage.
2. Autoimmune Diseases: In autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus, IL-6 contributes to immune system malfunctions. Overactive IL-6 signaling prompts the immune system to erroneously attack its own tissues, resulting in immune inflammation and tissue injury.
3. Cancer: IL-6 exhibits heightened levels in diverse cancers, including multiple myeloma, liver cancer, and lung cancer. It fosters cancer cell proliferation, survival, and metastasis, establishing an environment that evades immune recognition. This significantly influences cancer progression and therapeutic approaches.
4. Infections: During infections, IL-6 orchestrates vital roles within the immune response. It enhances the activation of immune cells and inflammatory responses, bolstering the body's resistance against pathogens. However, excessive IL-6 activation during viral infections like COVID-19 may trigger cytokine release syndrome (CRS), culminating in an overwhelming inflammatory reaction.
5. Drug Development: Given IL-6's pivotal role in various diseases, targeting IL-6 and its receptors has emerged as a promising avenue for drug development. Inhibitors of IL-6, such as those used to treat rheumatoid arthritis, are actively being explored for potential efficacy in cancer treatment.

Collectively, IL-6 exerts substantial influence on the development of diverse diseases. Understanding its intricate regulatory mechanisms in various contexts holds immense significance for advancing disease treatment and facilitating drug development.

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