Multiple isoforms of IL-8 are generated through both
alternative splicing and differential proteolytic cleavage. In humans,
alternative splicing generates an iso-form with an eleven aa substitution at
the C-terminus. Proteolytic processing results in N-terminal truncation of IL-8
and is likely a cell-specific event. For example, fibroblasts and endothelial
cells generate the 1-77 form by cleaving IL-8 following Glu21, while monocytes
and lymphocytes generate the 6-77 form by cleaving following Leu25. These
truncated forms generally show increased bioactivity, particularly through the
CXCR1 receptor. IL-8 can also undergo citrullination on Arg27 of the precursor,
a modification that increases its half-life and ability to induce leukocytosis.
A wide variety of cells secrete IL-8 including monocytes and neutrophils, fibroblasts
and keratinocytes, mast cells, visceral smooth muscle cells, dendritic cells,
type II great alveolar cells, and endothelial cells.
IL-8 bioactivity is mediated through two G-protein-coupled
receptors, termed CXCR1/IL-8 RA and CXCR2/IL-8 RB. CXCR1 is 45-50 kDa in size
and is used almost exclusively by IL-8. CXCR2 is 35-40 kDa in size and is used
by nearly all CXC chemokines. Both CXCR1 and CXCR2 constitutively associate
into functional homodimers. They can also heterodimerize, but these complexes
dissociate following IL-8 binding. CXCR2 responds to low concentrations of IL-8
and is principally associated with chemotaxis and MMP-9 release. CXCR1, in
contrast, responds to high concentrations of IL-8 and is associated with
respiratory burst and phospholipase D2 activation. Thus, CXCR2 ligation induces
leukocyte adhesion to activated vascular endothelium and migration to sites of
inflammation, while CXCR1 ligation primes neutrophil antimicrobial activity.
IL-8 can also form a complex with Serpin A1/alpha-1 Antitrypsin, and this
prevents IL-8 interaction with CXCR1.
In addition to its pro-inflammatory effects, IL-8 is
involved in angiogenesis and the pathogenesis of atherosclerosis and cancer. It
induces VEGF expression in vascular endothelial cells and functions as an
autocrine factor for EC growth and angiogenesis. It is upregulated in
atherosclerotic lesions and is elevated in the serum and cerebrospinal fluid
following myocardial infarction. In cancer, IL-8 promotes
epithelial-mesenchymal transition as well as tumor cell invasiveness and
metastasis.
Powered by Bioz
