IL-6: An Important Participant in the Inflammatory Cascade, One of the Most Functional Cytokines in Various Diseases Research!
On February 22, 2024, Cell Reports published a significant article titled "Insights into IL-6 Signaling Inhibition with Therapeutic Antibodies." This study highlights how antibodies like Tocilizumab and Sarilumab block the IL-6 pathway, effectively treating conditions such as rheumatoid arthritis, cytokine storms, and COVID-19 pneumonia [1].IL-6, a single-chain glycoprotein cytokine, is produced by a variety of cells and has a wide range of bioactive functions. A large number of studies have confirmed that IL-6 plays a key role in the regulation of systemic inflammatory response syndrome, chronic autoimmune diseases and tumor development. Therefore, IL-6, as one of the most functional cytokines, is becoming an important target for drug development!
1. What is IL-6?
1.1 The Structure of IL-6
Interleukin-6 (IL-6) stands as the pioneering member of the IL-6 family, initially recognized as B cell stimulator -2 (BSF-2). With a molecular weight of approximately 26 kDa, IL-6 is a phosphorylated glycoprotein comprising 212 amino acids, including a 28-amino-acid signal peptide sequence, encoded by a gene located on chromosome 7. Its structure comprises four helical bundles arranged in an "up-up-down-down" topology, forming three rings (two longer rings, A-B and C-D, along with a shorter B-C ring). Alongside IL-6, the IL-6 family encompasses IL-11 , IL-27 , OSM , LIF, CNTF , CT1 , CLCF1 , IL-35 , and IL-39. These members exhibit sequence diversity since they share a common receptor subunit known as glycoprotein 130 (GP130 ), facilitating signal transduction upon ligand binding [1-7].
1.2 The Expression and Function of IL-6
IL-6, a pivotal cytokine, is secreted by various immune cells like macrophages and infected T cells. Not limited to macrophages, other cell types such as intestinal cells, hepatocytes, and lung cells also contribute to its production. Essential for maintaining bodily equilibrium, IL-6 swiftly responds to disruptions like infection or tissue damage by triggering acute phase and immune responses, thereby aiding in host defense. However, excessive IL-6 synthesis or persistent imbalance can lead to pathological outcomes, including heightened inflammatory responses, disturbed immune function, and aberrant hematopoiesis. Since its discovery, IL-6 has been implicated in a spectrum of diseases ranging from stress-related conditions to pneumonia, immune disorders, cardiovascular ailments, and cancer [1-7].
2. What are the Receptors for IL-6?
IL-6 initially binds to IL-6 receptors, namely IL-6R /IL-6Rα (CD126), triggering the formation of a hexamer complex involving two ligand molecules, two α subunit molecules, and two β130 molecules, where the latter binds to GP130. IL-6 has two receptor types--IL-6R and sIL-6R--each initiating distinct signal transduction pathways: membrane receptors initiate classical signaling, while soluble receptors trigger trans-signaling, both necessitating GP130. Although GP130 is ubiquitously expressed, IL-6R/IL-6Rα is found only on specific cells like hepatocytes, neutrophils, monocytes, macrophages, and T and B lymphocytes. Soluble IL-6R and IL-6 complex facilitate IL-6 signal transduction in diverse cells (e.g., nerve cells, smooth muscle cells, and endothelial cells) where GP130 alone is present on the surface [8-10].
3. How's the Signaling Mechanisms Associated with IL-6?
IL-6 orchestrates signaling via its distinctive receptor system, engaging a cell surface type I receptor complex composed of IL-6R/IL-6Ra binding protein and the signal transduction element glycoprotein 130 (CD130). This complex activates various signaling pathways including JAK/STAT3 , PI3K/AKT /mTOR, RAS/RAF/MEK/ERK , YAP, and SHP2/RAS/MAPK, collectively recognized as the classical IL-6 signal transduction cascade [11].
3.1 IL-6's Classical Signal Transduction
In the classical IL-6 signaling pathway, key proteins like JAK, STAT3, and Ras play crucial roles. IL-6 activates JAK, leading to STAT3 phosphorylation and nuclear translocation, where it regulates gene expression for cell growth, differentiation, and survival. Additionally, IL-6 activates Ras, boosting MAPK activity and transcription factor engagement, essential for cell growth and immunoglobulin synthesis. It also activates the PI3K/PKB/Akt pathway, influencing cell functions [10-11]. In resting CD4? T cells, IL-6 triggers STAT3 activation, promoting the transcription of STAT3 and target genes, including Arid5a. Arid5a protects STAT3 mRNA from degradation by Regnase-1 , vital for sustaining IL-6 production and signaling transduction [12].
3.2 IL-6's Trans-Signaling Transduction
IL-6 exclusively binds to IL-6R, rendering cells lacking IL-6R unresponsive to IL-6. Nonetheless, membrane-bound IL-6R can be enzymatically cleaved, releasing soluble IL-6R (sIL-6R), facilitated mainly by ADAM17 and ADAM10 . This generation of sIL-6R broadens IL-6's reach due to widespread GP130 expression. Cells lacking IL-6R can still engage in signaling pathway via sIL-6R binding to GP130, termed IL-6 trans-signaling. Consequently, distinct IL-6 pathways govern various biological effects, including regulating white blood cell recruitment, tumor-associated inflammation, and contributing significantly to immune response, hematopoietic function, and acute phase homeostasis [11].
3.3 IL-6's Other Signal Transduction
In normal cells, various signals including IL-1 , TNF , IFNs, DNA and RNA viruses, and bacterial endotoxins regulate IL-6 production [13]. During acute inflammation, monocytes and macrophages activate IL-6 production via Toll-like receptors (TLR), while in chronic inflammation, T cells are major IL-6 sources. Studies demonstrate that the polynucleotide Poly I:C activates TLR3 , leading to IL-6 release and STAT3-mediated regulation of TLR2 expression [14]. Overall, IL-6 plays a multifaceted role in both physiological and pathological processes. The inhibition of IL-6 and its signaling pathways has emerged as an effective strategy for treating various diseases.
4. IL-6 and Disease-Related Research
4.1 IL-6 and Inflammation Research
4.1.1 IL-6 in Acute Inflammation Research
During early inflammation, the synthesis and release of IL-6 represent vital responses to injury or infection. IL-6 swiftly activates and disseminates throughout the body via the bloodstream, originating from local tissues. In the liver, IL-6 triggers various biological responses, notably the synthesis of acute phase proteins such as CRP , SAA , and fibrinogen [15-18].
These proteins play a pivotal role in combating infection and facilitating tissue repair by regulating the immune response and thwarting pathogen invasion. Moreover, by modulating the intensity and duration of inflammation, they contribute to maintaining tissue homeostasis. Thus, the timely release of IL-6 and the synthesis of acute phase proteins are indispensable for combating infection, repairing tissue damage, and regulating immune responses [15-18].
4.1.2 IL-6 in Chronic Inflammation Research
IL-6 assumes a multifaceted role in chronic inflammation, impacting various physiological processes. It regulates the skeletal system's homeostasis and influences osteoclast differentiation and activation, ultimately affecting bone density and structure, potentially leading to osteoporosis [19-20]. Additionally, IL-6 induces vascular endothelial growth factor (VEGF ), heightening vascular permeability—a hallmark of inflammatory diseases.
For instance, in rheumatoid arthritis, IL-6-induced VEGF overexpression correlates with increased synovial tissue permeability, exacerbating arthritis [21-22]. Moreover, IL-6 suppresses the production of albumin, fibronectin, and transferrin, potentially leading to complications like amyloidosis in chronic inflammatory diseases [23]. Thus, IL-6's multifunctional role extends beyond specific cell types, significantly impacting the entirety of inflammatory diseases and influencing diverse physiological processes such as bone health and vascular permeability.
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4.2 IL-6 in Nervous System Research
In recent years, beyond its role in inflammatory diseases, IL-6 has emerged as a significant player in the nervous system. Optimal IL-6 levels regulate neuronal development, differentiation, and survival, crucial for maintaining nervous system growth and function. However, under inflammatory stimuli or injury, the body produces excessive IL-6, exacerbating nerve cell injury through inflammatory effects [24-25].
Neonatal purulent meningitis (NPM), a common central nervous system infection in neonates, exhibits elevated levels of cytokines IL-6 and IL-10 in cerebrospinal fluid, indicating their involvement in NPM pathogenesis [24-25]. Moreover, IL-6 levels are notably increased in children with febrile convulsions, particularly in those with complex forms. While the IL-6 gene exhibits multiple loci, its relationship with febrile convulsion susceptibility remains inconclusive [26-28].
4.3 IL-6 in Advanced Stage of Tumor Research
IL-6 plays a crucial role in advanced cancer stages, much like other IL-6 family cytokines, its abnormal expression and disrupted receptor signaling correlate with poor clinical outcomes. It directly impacts cancer cell behavior and indirectly influences the tumor microenvironment. By activating pathways like STAT3, IL-6 promotes cancer cell growth, angiogenesis, metastasis, and invasion. Additionally, it supports cancer cell metastasis and the proliferation of cancer stem cells. Other family members such as IL-11 , LIF, and OSM also contribute to tumor growth. IL-6 levels closely relate to cancer prevalence and prognosis, potentially serving as an independent prognostic marker [29-30].
For example, increased serum IL-6 levels are linked to colorectal adenomas, with higher levels seen in advanced rectal cancer patients, closely tied to prognosis. However, IL-6 alone can't predict colorectal cancer status [31]. In gastric cancer, IL-6 levels in the gastric mucosa correlate with survival time, indicating its potential as a prognostic marker [32]. Elevated IL-6 in liver cancer tissues predicts poor prognosis independently [33]. IL-6 secretion triggers STAT3 phosphorylation, fueling prostate cancer cell proliferation and migration while hindering apoptosis and epithelial-mesenchymal transition (EMT) [34].
4.4 IL-6 in Other Related Diseases Research
High IL-6 levels raise the risk of coronary heart disease by promoting vascular smooth muscle cell transformation and intravascular calcium salt deposition [35–36]. Conversely, in inflammation, IL-6 reduces synovial inflammation and osteoarthritis cartilage damage by releasing inflammatory mediators from synovial membrane and chondrocytes [37]. It also inhibits proteoglycan and cartilage collagen synthesis and bone cell activity [38-39]. IL-6 is associated with conditions like meconium aspiration syndrome and sleep apnea-related pulmonary hypertension, requiring further investigation into its mechanisms [40-42].
Some studies are also investigating IL-6's role in other conditions. These include endothelial barrier dysfunction, myocardial negative inotropic effect, and VE-cadherin phosphorylation induced by vascular endothelial growth factor. IL-6's role in managing cytokine release syndrome with CAR-T cell therapy for cancers like acute lymphoblastic leukemia is also being explored [43-46]. Additionally, IL-6 signaling is implicated in limiting endotoxemia and obesity-related insulin resistance via the macrophage activation pathway [47–48]. Moreover, IL-6 promotes hepcidin production, impacting blood iron and zinc levels, potentially causing anemia and hypozinemia [49-50].
5. The Clinical Research Prospect of IL-6
IL-6 is a promising target in clinical research, primarily addressed through monoclonal antibodies against its receptor (IL-6R). Tocilizumab, among three approved drugs, neutralizes IL-6 activity by binding to IL-6R, effectively blocking signal transduction. Tocilizumab has demonstrated significant efficacy in treating diseases like rheumatoid arthritis and systemic arthritis. This approach is now being applied to various chronic autoimmune diseases, showing promise for broader application. Leading drug R&D countries like the United States and China are at the forefront, driving competitiveness and warranting attention. In the coming decade, IL-6 inhibitors are expected to tackle challenging diseases such as cytokine storms, potentially overcoming their refractory nature. Overall, drug development progress in this area is promising and highly feasible.
In Conclusion:
IL-6, a pivotal cytokine, influences diverse physiological processes and pathological conditions. Its dysregulation is associated with various diseases, from inflammation and autoimmune disorders to cancer and cardiovascular ailments. Beyond, IL-6 plays multifaceted roles in immune response modulation, tissue repair, and disease progression. Ongoing research underscores IL-6's significance as a therapeutic target, with potential applications across a spectrum of challenging conditions, paving the way for innovative treatment strategies in the future.
6. CUSABIO IL6 Recombinant Proteins and Antibodies for Research Use
To assist pharmaceutical companies in their clinical research on IL6 in systemic inflammatory response syndrome, chronic autoimmune diseases and tumor, CUSABIO launched IL6 (CSB-YP011664HU ) active protein products to assist your investigation of the mechanism of IL6 or its potential clinical value.
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