Interleukin 8 (IL8) is a proinflammatory CXC chemokine (CXCL8) that promotes neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface G protein-coupled receptors (CXCR1 and CXCR2). IL8 expression is increased in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages. A growing body of research indicates that IL8 is a key regulator in the tumor microenvironment.
(Data source: Bakouny Z, et al. Nat Med. 2020)
IL8 structure:
The IL8 gene encodes a 99-amino acid protein that is subsequently processed into a signaling secretory protein consisting of 77 amino acids in non-immune cells or 72 amino acids in monocytes and macrophages. IL8 is also secreted by fibroblasts and malignant tumor cells in response to various environmental stresses, such as hypoxia and chemotherapeutic drugs. The CXCL8 monomer (Figure 1A, B) has an unstructured, flexible N-terminal domain preceding the first two cysteine residues, followed by an extended irregular loop consisting of a small helix and three antiparallel β-strands, culminating in a carboxyl-terminal α-helix. IL8 exists as a monomer or dimer, binding to two cell surface receptors, CXCR1 and CXCR2, respectively.
(Data source Cambier S, et al. Cell Mol Immunol. 2023)
IL8 signaling pathway and regulation:
IL8 has a greater affinity for CXCR1. Binding to CXCR1 or CXCR2 triggers conformational changes, leading to dissociation of the cytoplasmic G protein-coupled subunits Gα and Gβ/γ, promoting the activation of multiple signaling pathways, including MAPK, PI3K/Akt, and PLC/PKC. In addition to proinflammatory genes, MAPK signaling leads to the transcription of numerous genes that promote cell proliferation and survival. IL8-induced MAPK and PI3K activation promotes the induction of adhesion molecules, such as Mac-1 and integrins, which are key mediators of chemotaxis. Furthermore, the production of the second messenger molecule 3,4,5-inositol triphosphate (IP3) leads to the release of intracellular calcium from endoplasmic reticulum stores, ultimately leading to neutrophil degranulation, a process that mediates the release of antimicrobial and cytotoxic molecules. IL8 recruits neutrophils through a complex series of signaling events and the secretion of adhesion molecules, thereby driving chemotaxis.
(Data source: Druszczyńska M, et al. Int J Mol Sci. 2022)
Clinical value of IL8:
The angiogenic and inflammatory effects of IL8 promote uncontrolled tumor growth and metastasis: overexpression of IL8 in the tumor (microenvironment) promotes the migration of endothelial cells and the formation of new blood vessels in the tumor by infiltrating immune cells, stromal cells, and tumor cells themselves. In addition, IL8 can directly stimulate tumor (microenvironment) cells that express CXCR1 or CXCR2, stimulating their survival, proliferation, and migration, further enhancing tumor expansion.
(Data source: Pavord ID, et al. Allergy. 2022)
Because IL8 is associated with the tumor microenvironment and tumor progression, inhibiting IL8 may reduce these tumorigenic effects. Several drugs and therapeutic strategies are being developed to block IL8 or inhibit its receptor CXCR1/2 signaling to improve inflammatory status and tumor treatment outcomes. ABX-IL8 and HuMax-IL8 are among the most studied. Recent studies have also demonstrated that IL8 and its receptor blockers have significant clinical potential as single agents or in combination.
(Data source: Cambier S, et al. Cell Mol Immunol. 2023)
