Interleukin 8

CXCL8
Available structures
PDB	Human UniProt search: PDBe RCSB
List of PDB id codes
	3IL8, 1ICW, 1IKL, 1IKM, 1IL8, 1ILP, 1ILQ, 1QE6, 1ROD, 2IL8, 4XDX
Identifiers
Aliases	CXCL8, chemokine (C-X-C motif) ligand 8, GCP-1, GCP1, LECT, LUCT, LYNAP, MDNCF, MONAP, NAF, NAP-1, NAP1, IL8, C-X-C motif chemokine ligand 8, Interleukin-8, SCYB8
External IDs	OMIM: 146930; HomoloGene: 47937; GeneCards: CXCL8; OMA:CXCL8 - orthologs
Gene location (Human)
Chr.	Chromosome 4 (human)
End	73,743,716 bp
RNA expression pattern
	Top expressed in
	periodontal fiber; ; granulocyte; ; beta cell; ; cartilage tissue; ; olfactory zone of nasal mucosa; ; monocyte; ; mucosa of paranasal sinus; ; bone marrow cells; ; sperm; ; gallbladder;
	n/a
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	cytokine activity; protein binding; interleukin-8 receptor binding; chemokine activity;
Cellular component	extracellular region; intracellular anatomical structure; extracellular space;
Biological process	G protein-coupled receptor signaling pathway; intracellular signal transduction; chemokine-mediated signaling pathway; cellular response to tumor necrosis factor; receptor internalization; cellular response to fibroblast growth factor stimulus; response to endoplasmic reticulum stress; positive regulation of angiogenesis; regulation of single stranded viral RNA replication via double stranded DNA intermediate; PERK-mediated unfolded protein response; induction of positive chemotaxis; chemotaxis; regulation of cell adhesion; immune response; cellular response to interleukin-1; angiogenesis; positive regulation of neutrophil chemotaxis; inflammatory response; negative regulation of G protein-coupled receptor signaling pathway; response to molecule of bacterial origin; cellular response to lipopolysaccharide; embryonic digestive tract development; signal transduction; negative regulation of cell population proliferation; calcium-mediated signaling; regulation of entry of bacterium into host cell; defense response; neutrophil chemotaxis; neutrophil activation; antimicrobial humoral immune response mediated by antimicrobial peptide; regulation of signaling receptor activity; cytokine-mediated signaling pathway; leukocyte chemotaxis;
	Sources:Amigo / QuickGO
Orthologs
	3576
	n/a
	ENSG00000169429
	n/a
	P10145
	n/a
	NM_000584; NM_001354840
	n/a
	NP_000575; NP_001341769
	n/a
	Wikidata
View/Edit Human

Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells^[3] and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel–Palade bodies.^[4]^[5] In humans, the interleukin-8 protein is encoded by the CXCL8 gene.^[6] IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms.^[7] In culture, a 72 amino acid peptide is the major form secreted by macrophages.^[7]

There are many receptors on the surface membrane capable of binding IL-8; the most frequently studied types are the G protein-coupled serpentine receptors CXCR1 and CXCR2. Expression and affinity for IL-8 differs between the two receptors (CXCR1 > CXCR2). Through a chain of biochemical reactions, IL-8 is secreted and is an important mediator of the immune reaction in the innate immune system response.

Function

IL-8, also known as neutrophil chemotactic factor, has two primary functions. It induces chemotaxis in target cells, primarily neutrophils but also other granulocytes, causing them to migrate toward the site of infection. IL-8 also stimulates phagocytosis once they have arrived. IL-8 is also known to be a potent promoter of angiogenesis. In target cells, IL-8 induces a series of physiological responses required for migration and phagocytosis, such as increases in intracellular Ca²⁺, exocytosis (e.g. histamine release), and the respiratory burst.

IL-8 can be secreted by any cells with toll-like receptors that are involved in the innate immune response and has been demonstrated to be a signatory chemokine of CR2+ naive T cells, also known as recent thymic emigrants.^[8]^[9]^[10] Usually, it is the macrophages that see an antigen first, and thus are the first cells to release IL-8 to recruit other cells. Both monomer and homodimer forms of IL-8 have been reported to be potent inducers of the chemokine receptors CXCR1 and CXCR2. The homodimer is more potent, but methylation of Leu25 can block the activity of homodimers. IL-8 is a member of the CXC chemokine family. The genes encoding this and the other ten members of the CXC chemokine family form a cluster in a region mapped to chromosome 4q.^[6]

IL-8 is believed to play a role in the pathogenesis of bronchiolitis, a common respiratory tract disease caused by viral infection.^{[citation needed]}

Another key function of the cell signalling stimulated by IL-8, is the initiation of the oxidative burst.^[11] This process allows the build up of proteolytic enzymes and reactive oxygen species (ROS) which are necessary to break down the ECM and basement membrane. These are released in secretory granules, along with more integrins. The release of ROS and damaging enzymes is regulated to minimise host damage, but continues to reach site of infection at which it will carry out its effector functions.^[12]

IL-8 mediated chemotaxis of the neutrophil

IL-8 is the primary cytokine involved in the recruitment of neutrophils to the site of damage or infection; in a process called chemotaxis. A number of variables are essential for the successful chemotaxis of neutrophils, including the increased expression of high affinity adhesion molecules to secure the neutrophil to the endothelium near the affected site (and is therefore not washed away into the circulatory system), and that the neutrophil can digest its way through the basement membrane and the extracellular matrix (ECM) to reach affected site. IL-8 plays a key role in inducing the cell signalling necessary to bring about these changes.^[13]

Firstly, at the site of infection histamine release causes vasodilation of the capillaries near the injured area which slows down the blood flow in the region and encourages leukocytes, such as neutrophils, to come closer to the endothelium, and away from the centre of the lumen where the rate of blood flow is highest. Once this occurs weak interactions are made between the selectins expressed on the neutrophil and endothelial cells (expression of which is also increased through the action of IL-8 and other cytokines). On the neutrophil these are: L selectins, and on the endothelial cell: P and E selectins. This causes the "rolling" phase of chemotaxis.

Once the neutrophil is rolling along the endothelium, it will come into contact with a IL-8 molecule expressed on the surface which stimulates the cell signalling pathway, mediated through a G-coupled-protein-receptor. The binding of IL-8 to CXCR1/2 on the neutrophil stimulates the neutrophils to upregulate their expression of the integrin, LFA-1 (Lymphocyte function-associated antigen 1), which takes part in high affinity bonding with ICAM-1 (Intercellular Adhesion Molecule 1) receptors expressed on the endothelium. The expression and affinity of LFA-1 is significantly increased to maximise binding. This causes the neutrophil to slow down more until it is stationary.^[13]

Target cells

While neutrophil granulocytes are the primary target cells of IL-8, there are a relatively wide range of cells (endothelial cells, macrophages, mast cells, and keratinocytes) that respond to this chemokine. The chemoattractant activity of IL-8 in similar concentrations to vertebrates was proven in Tetrahymena pyriformis, which suggests a phylogenetically well-conserved structure and function for this chemokine.^[14]

Clinical significance

Interleukin-8 is a key mediator associated with inflammation where it plays a key role in neutrophil recruitment and neutrophil degranulation.^[15] As an example, it has been cited as a proinflammatory mediator in gingivitis^[16] and psoriasis.

Interleukin-8 secretion is increased by oxidant stress, which thereby cause the recruitment of inflammatory cells and induces a further increase in oxidant stress mediators, making it a key parameter in localized inflammation.^[17] IL-8 was shown to be associated with obesity.^[18]

IL-8 has also been implied to have a role in colorectal cancer by acting as an autocrine growth factor for colon carcinoma cell lines^[19] or the promotion of division and possible migration by cleaving metalloproteinase molecules.^[20] It has also been shown that IL-8 plays an important role in chemoresistance of malignant pleural mesothelioma by inducing expression of transmembrane transporters.^[21]

If a pregnant mother has high levels of interleukin-8, there is an increased risk of schizophrenia in her offspring.^[22] High levels of Interleukin 8 have been shown to reduce the likelihood of positive responses to antipsychotic medication in schizophrenia.^[23]

IL-8 has also been implicated in the pathology of cystic fibrosis. Through its action as a signalling molecule IL-8 is capable of recruiting and guiding neutrophils to the lung epithelium. Overstimulation and dysfunction of these recruited neutrophils within the airways results in release of a number of pro-inflammatory molecules and proteases resulting in further damage of lung tissue.^[24]

Some benzodiazepines have inhibitory effects on the adenosine A2B receptor mediated secretion of interleukin-8 in human mast cells. In a 2013 study, diazepam, 4′-chlorodiazepam and flunitrazepam markedly reduced NECA-induced interleukin-8 production in that order of potency, whereas clonazepam showed only a modest inhibition.^[25]

Regulation of expression

The expression of IL-8 is negatively regulated by a number of mechanisms. MiRNA-146a/b-5p indirectly represses IL-8 expression by silencing the expression of IRAK1.^[26] Additionally, the 3'UTR of IL-8 contains a A/U-rich element that makes it extremely unstable under certain conditions. IL-8 and other inflammatory cytokines form a vicious cycle with the transcription factor NF-κB in cystic fibrosis.^[27] NF-κB regulation represents a novel anti-IL-8 therapy for use in inflammatory diseases such as cystic fibrosis. Pathways leading to the induction of ribosomal protein S6 (rpS6) phosphorylation have also been found to enhance IL-8 protein synthesis. This translational control of IL-8 expression is dependent on A/U-rich proximal sequences (APS), which are found in the 3'UTR of IL-8 immediately after the stop codon.^[28]

Nomenclature

IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the International Union of Immunological Societies,.^[29] Its approved HUGO gene symbol is CXCL8. Its receptors were similarly renamed:

Interleukin 8 receptor, alpha — CXCR1
Interleukin 8 receptor, beta — CXCR2

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000169429 – Ensembl, May 2017
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^ Wolff B, Burns AR, Middleton J, Rot A (November 1998). "Endothelial cell "memory" of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies". The Journal of Experimental Medicine. 188 (9): 1757–1762. doi:10.1084/jem.188.9.1757. PMC 2212526. PMID 9802987.
^ Utgaard JO, Jahnsen FL, Bakka A, Brandtzaeg P, Haraldsen G (November 1998). "Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells". The Journal of Experimental Medicine. 188 (9): 1751–1756. doi:10.1084/jem.188.9.1751. PMC 2212514. PMID 9802986.
^ ^a ^b Modi WS, Dean M, Seuanez HN, Mukaida N, Matsushima K, O'Brien SJ (January 1990). "Monocyte-derived neutrophil chemotactic factor (MDNCF/IL-8) resides in a gene cluster along with several other members of the platelet factor 4 gene superfamily". Human Genetics. 84 (2): 185–187. doi:10.1007/BF00208938. PMID 1967588. S2CID 2217894.
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^ Pekalski ML, García AR, Ferreira RC, Rainbow DB, Smyth DJ, Mashar M, et al. (August 2017). "Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2". JCI Insight. 2 (16). doi:10.1172/jci.insight.93739. PMC 5621870. PMID 28814669.
^ van den Broek T, Delemarre EM, Janssen WJ, Nievelstein RA, Broen JC, Tesselaar K, et al. (2016-02-22). "Neonatal thymectomy reveals differentiation and plasticity within human naive T cells". Journal of Clinical Investigation. 126 (3): 1126–1136. doi:10.1172/JCI84997. ISSN 0021-9738. PMC 4767338. PMID 26901814.
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^ Milosevic, V. et al. Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.Int. J. Cancer, https://doi.org/10.1002/ijc.32419
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^ Reeves EP, Williamson M, O'Neill SJ, Greally P, McElvaney NG (June 2011). "Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis". American Journal of Respiratory and Critical Care Medicine. 183 (11): 1517–1523. doi:10.1164/rccm.201101-0072oc. PMID 21330456.
^ Hoffmann K, Xifró RA, Hartweg JL, Spitzlei P, Meis K, Molderings GJ, et al. (January 2013). "Inhibitory effects of benzodiazepines on the adenosine A(2B) receptor mediated secretion of interleukin-8 in human mast cells". European Journal of Pharmacology. 700 (1–3): 152–158. doi:10.1016/j.ejphar.2012.12.003. PMID 23266380.
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