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Interleukin-8 signalling

Interleukin-8 signalling

IL-8 Overview

Interleukin-8 (IL-8), also known as CXCL8, was discovered over 30 years ago as a small molecule that could promote chemotaxis and induce the production of both superoxide and hydrogen peroxide (H202) . IL-8 is now recognized as a chemokine, which are small chemoattractant molecules that are secreted by cells of the immune system. Chemokines induce integrin expression and primarily attract leukocytes to the site of infection, although their roles have been discovered to be much more diverse.

44 chemokines and 23 chemokine receptors have been identified to date. Structurally, IL-8 contains two N-terminal cysteine motifs, which classify it as a CXCL family member. These cysteine motifs are separated by an amino acid which is essential for the specific binding of IL-8 to its membranous receptors CXCR1 and CXCR2. Classification of CXCR1 and CXCR2 determined their expression on several cell types, including endothelial and epithelial cells, as well as fibroblasts and neutrophils. IL-8 is primarily produced by macrophages, epithelial cells, and endothelial cells, and has an important role in cell migration, targeting neutrophils.

The discovery of IL-8 and its function as a chemokine has significantly contributed to our understanding of the immune system's response to infections and inflammation. Over the years, research on IL-8 has unveiled its involvement in various disease processes, including chronic inflammatory conditions and certain types of cancers. Therapeutic targeting of IL-8 and its receptors, CXCR1 and CXCR2, has emerged as a promising approach in managing these diseases.

IL-8 Signalling

IL-8 can binds to the cell surface receptors CXCR1 and CXCR2, with a greater affinity of IL-8 for CXCR1, with the ligation of IL-8 to CXCR1 induces chemotactic signalling downstream. The binding of IL-8 to CXCR1 or CXCR2 triggers a conformational change and leads to the dissociation of cytoplasmic G-coupled protein subunits, Ga and Gbg, facilitating the activation of a variety of signalling pathways, including the mitogen-associated protein kinase (MAPK), phosphatidyl-inositol 3’ kinase/Akt (PI3K/Akt), phospholipase C/protein kinase C (PLC/PKC) pathways. MAPK signalling leads to the transcription of multiple genes that promote cell proliferation and survival, in addition to pro-inflammatory genes. IL-8 – induced activation of both MAPK and PI3K facilitates the induction of adhesion molecules, such as Mac-1 and integrins, which are critical molecules for mediating chemotaxis. Furthermore, the production of the second messenger molecule 3,4,5-inositol triphosphate (IP3) leads to the release of intracellular calcium from the endoplasmic reticulum stores, which culminates in the degranulation of neutrophils, a process mediating the release of antimicrobial, cytotoxic molecules. Overall, IL-8 drives chemotaxis by recruiting neutrophils via a series of complex signalling processes and the secretion of adhesion molecules. Transcription of IL-8 is induced by stimulation with TNFa , LPS, IL-1, or by viral infection.

IL-8 in Pathogenesis

It has been long established that elevated levels of IL-8 contribute to the pathogeneses of multiple inflammatory diseases, such as inflammatory bowel disease. During chronic inflammatory pathogenesis, increased infiltration of neutrophils concurrent with increased levels of IL-8 is noted. Targeting IL-8 production via the inhibition of NF-kB activation leads to reduce IL-8 transcription in intestinal epithelial cells lead to reduced inflammation in the gastrointestinal tract. Moreover, IL-8 induces malignancies, angiogenesis, and cellular invasion. In vitro experiments shave shown that over expression of IL-8 in colon cancer cell lines promotes cell proliferation, angiogenesis and migration. Recent studies have demonstrated that IL-8 and IL-6 signal synergistically to enhance cellular migration and promotes metastasis, with dual inhibition of both IL-8 and IL-6 leading to a reduced metastatic phenotype in breast cancer. High levels of IL-8 has also been associated with poor response to chemotherapy, and downregulating IL-8 levels reduced chemoresistance in hepatocellular carcinoma. Interestingly, CXCR1 and CXCR2 have been identified on immune cells in the CNS; astrocytes and microglia, as well as on neurons. Recently, the activation of microglia and astrocytes facilitates the chemokine-induced infiltration of neutrophils into the CNS in response to b-amyloid pathogeneses has been implicated in Alzheimer’s disease pathology.

Targeting IL-8 as a Therapeutic Strategy

IL-8 inhibition has been explored as a therapeutic target yielding promising results. The use of monoclonal antibody to neutralize IL-8 has been demonstrated to reduce the IL-8 – induced detrimental effects in inflammatory pathogeneses. Targeting the IL-8 receptors is another approach, and notably, it is required that both CXCR1 and CXCR2 are inhibited in order to eliminate the harmful effects of IL-8. Several small molecule inhibitors of CXCR1/CXCR2 have been developed, including repertaxin, SCH479833 (Merck), and SCH527123 (Merck), which have all shown positive anti-tumour results in cases of melanoma, breast cancer and colon cancer.

In addition to its role in cancer, recent research has highlighted the significance of IL-8 in various other diseases, such as chronic inflammatory disorders, autoimmune conditions, and even certain viral infections. This expanded understanding of IL-8's involvement in diverse pathological processes opens up new possibilities for therapeutic interventions targeting this cytokine. However, due to the pleiotropic nature of many cytokines, including IL-8, it is essential to exercise caution when developing signalling inhibitors.

As IL-8 – induced neutrophil invasion is a homeostatic part of immunosurveillance, the effects of IL-8 inhibitors must be carefully monitored and balanced when developing therapeutics. Striking the right balance between suppressing IL-8-induced detrimental effects while preserving its crucial immunomodulatory functions remains a critical challenge. Nonetheless, with the advancement of targeted drug delivery systems and a better understanding of the intricacies of the IL-8 signaling pathway, researchers are hopeful that the development of more precise and effective IL-8-targeted therapies is on the horizon.

In conclusion, IL-8 signaling plays a central role in mediating inflammation and immune responses, making it a compelling target for therapeutic intervention. The inhibition of IL-8 and its receptors has shown promising results in combatting inflammatory pathogeneses and various cancers, offering new avenues for the development of targeted therapies. However, the pleiotropic nature of IL-8 necessitates careful consideration to avoid disrupting crucial immunomodulatory functions. As research progresses and our understanding of IL-8's complex interactions deepens, there is hope for the emergence of more precise and effective IL-8-targeted treatments. Collaborative efforts between diverse scientific disciplines will be essential in unlocking the full potential of IL-8 signaling modulation, paving the way for improved treatments and better patient outcomes in a wide range of diseases and conditions.

Written by Pragna Krishnapur

Pragna Krishnapur completed her bachelor degree in Biotechnology Engineering in Visvesvaraya Technological University before completing her masters in Biotechnology at University College Dublin.

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23rd Jul 2023 Pragna Krishnapur, MSc

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