Interleukin 8 (IL-8), also known as GCP-1, NAP-1 and CXCL8, is a member of the CXC family of chemokines. So far, 15 members of the CXC family have been found in humans, ranging from 8 to 12 kDa. Most of the family's genes are on chromosome 4. IL-8 selectively stimulates the ability of neutrophils and T-cells to invade injured and inflammatory tissues. IL-8 derived from peripheral blood monocytes is a 10 kDa protein that has at least 4 forms (sized 77, 72, 70 and 69 amino acids) which differ in the lengths of their amino terminal ends and form readily into dimers in solution. The two cysteine bridges present are essential for the biological activity of IL-8. Exogenous stimuli such as LPS, but also IL-1, TNF-α and TNF-β, induce IL-8 secretion in a variety of different cell types including monocytes, endothelial and epithelial cells, mononuclear cells, peripheral blood, skin fibroblasts, keratinocytes, neutrophils, hepatocytes, synovial cells, and T cells.
When IL-8 is injected subcutaneously in rats, both lymphocytes and neutrophils migrate to the injection site within 3 hours. At low doses, only lymphocytes migrate to the injection site, whereas at higher doses, mainly neutrophils migrate. It has been found that T cells are 10 times more sensitive to IL-8 than neutrophils. IL-8 exerts its actions through specific cell membrane receptors that have two cytokine binding sites. Receptor density is determined by cell type and ranges from 300 in T cells to 20,000 in neutrophils. Upon binding of IL-8 to its receptor, they move together within the cell. In addition to its chemotactic action, IL-8 has other different characteristics. In neutrophils it triggers the secretion of peroxide anions and lysosomal enzymes and thereby indirectly increases the permeability of blood vessels. IL-8 also increases fungicidal activity against Candida albicans. Neutrophils are more easily released from the bone marrow under the influence of this cytokine. In vitro, IL-8 stimulates the expression of Mac-1, CR1, p150, and LFA-1 in neutrophils, allowing their adhesion to activated vascular endothelial cells expressing ICAM-1. This event may be responsible for the accumulation of neutrophils at the injection sites of IL-8. Other findings suggest that IL-8-derived endothelial cells can function to mitigate inflammatory events at the interface between the vessel wall and blood by inhibiting adhesion of neutrophils to cytokine-activated endothelial cells. Therefore, these cells appear to be protected from the damage that neutrophils would cause. In basophils, besides its chemotactic effects, IL-8 stimulates the release of histamine in atopic as well as healthy individuals.
The ability of IL-8 to stimulate neutrophil motility through the endothelial monolayer in vitro supports the central role of this molecule in the accumulation of neutrophils in inflammatory lesions in vivo. The data indicate that IL-8 may be involved in the pathogenesis of rheumatoid arthritis through induction of neutrophil-mediated cartilage damage and psoriasis.
The involvement of IL-8 has been shown in a wide range of clinical-pathological conditions: adult respiratory distress syndrome, asthma, bacterial infections, bladder cancer, transfusion incompatibility, contact dermatitis, emphysema syndrome, immune vasculitis, inflammatory bowel disease, influenza virus infection, Jarisch-Herxheimer reaction, central nervous system malignancies, myocardial infarction, placenta infection, sepsis and uveitis.
Because of the known biological properties of IL-8, this cytokine, especially in combination with other neutrophil activating agents, may prove useful in the treatment of patients suffering from granulocytopenia, severe infections against which antibiotics are ineffective and immune from HIV.
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