IL-8 Signaling

Interleukin 8 (IL-8) is a member of the C-X-C family of chemokines that plays a central role in angiogenesis, tumor growth and inflammation. The cell surface receptors for IL-8 which are coupled to G proteins include CXCR1 (IL-8 receptor type 1) and the CXCR2 (IL-8 receptor type 2). While the CXCR1 is selectively activated by IL-8 only, CXCR2 responds to several additional chemokines. The IL-8 receptors are expressed on several cell types like neutrophils, endothelial cells, monocytes and tumor cells.Angiogenesis is a multistep process including endothelial cell proliferation, migration, gap formation, capillary tube formation, endothelial cell survival and death. IL-8 plays a key role in many aspects during the early stages of the angiogenic process. Several kinases like Extracellular signal regulated kinase (ERK), p21 activated kinase (PAK) and LIM kinase are activated by IL-8 signaling and regulate the cytoskeletal response in angiogenesis. IL-8 also induces nuclear transcription factor-kappa B (NF-κB) through a TRAF6-dependent pathway, leading to the transcription of proangiogenic genes like ICAM and VCAM. The IL-8 mediated physical interaction between CXCR1, CXCR2 and vascular endothelial growth factor receptor (VEGFR) leads to the transactivation and phosphorylation of the latter, in a VEGF-independent manner. The formation of this complex results in the activation of Rho kinase (ROCK) which promotes endothelial gap formation. Similar to VEGFR, IL-8-induced transactivation of the EGFR is mediated by the CXCR2 and involves cathepsin B. Stimulation of EGFR leads to the activation of Phosphoinositide 3 kinase (PI3K) which facilitates endothelial cell migration. The upregulation of matrix metalloproteinase (MMP2 and MMP9) expression by IL-8 is another mechanism that leads to increased endothelial cell migration. Migration and gap formation in endothelial cells lead to increased vascular permeability.Tumor growth and metastasis is related to neovascularization or angiogenesis within the tumor tissue. IL-8 upregulates the expression of genes involved in tumor growth (EGFR), angiogenesis (VEGF) and tumor invasion (MMP2 and MMP9). Additionally, IL-8 enhances cell proliferation by activating cyclin D via a protein kinase B (PKB/Akt) mediated mechanism.Activation by IL-8 can trigger inflammation in cells like neutrophils leading to chemotaxis, the respiratory burst, granule release, and increased cell adhesion. The RAS/RAF/ERK1/2 pathway is activated by IL-8 resulting in neutrophil degranulation releasing proteins like myeloperoxidase (MPO) and defensins (HNP) that play an antimicrobial role. IL-8 activation of phospholipase D (PLD) triggers nucleotide adenosine phosphate dehydrogenase (NADPH) leading to respiratory burst. Chemotaxis is triggered by the several IL-8 activated kinases like PKB/Akt, focal adhesion kinase (FAK) and protein tyrosine kinase 2 (PYK2).This pathway highlights the important components of IL-8 signaling.