Interleukin-8

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Interleukin-8
Interleukin-8
Ribbon model of the CXCL8 as a dimer according to PDB  1il8

Existing structural data : 1icw , 1ikl , 1ilp , 1ilq , 1qe6 , 2il8 , 3il8

Properties of human protein
Mass / length primary structure 72 AS ; 8.4  kDa
Precursor 99 AS
Identifier
Gene names IL8  ; CXCL8; MDNCF; NAP-1; MONAP; GCP-1; Emoctakin
External IDs
Occurrence
Homology family Small inducible cytokines
Parent taxon Vertebrates
Exceptions mouse
Orthologue (human)
Entrez 3576
Ensemble ENSG00000169429
UniProt P10145
Refseq (mRNA) NM_000584
Refseq (protein) NP_000575
Gene locus Chr 4: 73.74 - 73.74 Mb
PubMed search 3576

Interleukin-8 (short: IL-8 ) or CXCL8 (for CXC-motif chemokine 8 ) is an endogenous messenger substance from the group of CXC-motif chemokines . CXCL8 is produced in particular by endothelial cells, monocytes, epithelial cells and fibroblasts . As an inflammation mediator , this cytokine is involved in the chemotactic recruitment of leukocytes, in particular neutrophils, into the inflamed tissue. In addition, CXCL8 is an angiogenesis factor and as such is involved in the formation and regeneration of blood vessels.

It was discovered in 1987 by Marco Baggiolini and others at the University of Bern .

biochemistry

genetics

The human Cxcl8 gene on chromosome 4 in the CXC chemokine cluster region on gene locus q13-21 encodes a precursor protein consisting of 99 amino acids . There is also a regulatory sequence with binding sites for the transcription factors AP-1 , NF-κB , C / EBP , which is used to control gene expression . The protein biosynthesis of CXCL8 is thus induced by activators of these transcription factors, such as interleukin 1 , interleukin 3 , interleukin 6 , tumor necrosis factor-α , interferon-γ , GM-CSF , lipopolysaccharides , reactive oxygen species and other cellular stress factors, while the anti-inflammatory cytokines Interleukin-4 and Interleukin-10 inhibit its biosynthesis.

Protein structure

From the precursor protein consisting of 99 amino acids, a form of CXCL8 consisting of 79 amino acids is released after cleavage of a signal sequence . This peptide is subject to further extracellular modifications at its N-terminus, so that various functional isoforms with 69 to 79 amino acids are formed. The dominant variant produced by immune cells consists of 72 amino acids, while a variant consisting of 77 amino acids is mainly produced by non-immune cells.

Like almost all chemokines, CXCL8 is a basic peptide. It contains four conserved cysteines, each linked by two disulfide bridges . CXCL8 is available in relevant quantities as a dimer, the monomeric form of the protein being sufficient for its biological effect.

Signal transduction

CXCL8 mediates its effects by binding to and activating the G-protein-coupled receptors CXCR1 and CXCR2 . By activating G proteins , these receptors trigger a signal transduction cascade that includes activation of adenylyl cyclases , MAP kinases and an intracellular increase in Ca 2+ concentration. In addition, CXCL8 binds to the structurally related DARC . However, its function is largely unclear.

function

immune system

Neutrophils are an important target of the chemokine . The main biological effects of IL-8 on granulocytes include the promotion of chemotaxis, the stimulation of the expression of adhesion molecules and the activation with the release of oxygen radicals and granules, which are mediated via the chemokine receptors CXCR1 and CXCR2 . This ensures that primarily neutrophils arrive at the focus of infection using the IL-8 gradient.

Angiogenesis

The pro-angiogenic effect of CXCL8 is based on the effect on endothelial cells . As a chemotactic cytokine, CXCL8 promotes the migration of endothelial cells into the extracellular matrix of the tissue. At the same time, CXCL8 has an anti- apoptotic effect on endothelial cells and promotes their proliferation with the formation of capillary structures. This mechanism is sustained by the CXCL8-induced release of extracellular matrix-degrading metalloproteases . This effect plays an important role during menstruation and wound healing . The pro-angiogenic effect is also of crucial importance for the supply and thus the growth of tumors.

Individual evidence

  1. ↑ Brat DJ, Bellail AC, Van Meir EG: The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis . In: Neuro-Oncology . 7, No. 2, April 2005, pp. 122-33. doi : 10.1215 / S1152851704001061 . PMID 15831231 . PMC 1871893 (free full text).
  2. ↑ Hoffmann E, Dittrich-Breiholz ​​O, Holtmann H, Kracht M: Multiple control of interleukin-8 gene expression . In: J. Leukoc. Biol . 72, No. 5, November 2002, pp. 847-55. PMID 12429706 .
  3. ↑ Baggiolini M, Dewald B, Moser B: Interleukin-8 and related chemotactic cytokines - CXC and CC chemokines . In: Adv. Immunol. . 55, 1994, pp. 97-179. PMID 8304236 .
  4. ↑ Xie K: Interleukin-8 and human cancer biology . In: Cytokine Growth Factor Rev. . 12, No. 4, December 2001, pp. 375-91. PMID 11544106 .
  5. ^ A b Baggiolini M, Clark-Lewis I: Interleukin-8, a chemotactic and inflammatory cytokine . In: FEBS Lett . . 307, No. 1, July 1992, pp. 97-101. PMID 1639201 .
  6. ↑ Baldwin ET, Weber IT, St Charles R, et al. : Crystal structure of interleukin 8: symbiosis of NMR and crystallography . In: Proc. Natl. Acad. Sci. USA . 88, No. 2, January 1991, pp. 502-6. PMID 1988949 . PMC 50839 (free full text).
  7. ↑ Rajarathnam K, Sykes BD, Kay CM, et al. : Neutrophil activation by monomeric interleukin-8 . In: Science (journal) . 264, No. 5155, April 1994, pp. 90-2. PMID 8140420 .
  8. ↑ Li A, Dubey S, Varney ML, Dave BJ, Singh RK: IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis . In: J. Immunol. . 170, No. 6, March 2003, pp. 3369-76. PMID 12626597 .