Interleukin-8: An autocrine inflammatory mediator

Interleukin-8 (IL-8), a pro-inflammatory chemokine, induces trafficking of neutrophils across the vascular wall. The release of IL-8 is triggered by i nflammatory signals from a large variety of cells. The diversity in the cel lular source indicates pleiotropy of its functions. IL-8 plays a key role i n host defense mechanism through its effects on neutrophil activation, but a continued presence of IL-8 in circulation in response to inflammatory con ditions may lead to a variable degree of tissue damage. Like most of the pe ptide hormones or mediators, IL-8 transmits its signals through distinct ce ll surface receptors. The membrane spanning heptahelical IL-8 receptor is c oupled with the effector enzyme(s) through the intermediacy of heterotrimer ic GTP-binding regulatory proteins. A growing number of studies demonstrate d regulation of IL-8 activity by pertussis toxin treatment, implying a role of pertussis toxin sensitive G proteins (Gi), in IL-8 induced effects. IL- 8 induced activation of G-protein results in activation of phospholipase C beta(2) (PLC beta(2)). This enzyme catalyzes the hydrolysis of membrane pho sphoinositides to yield diacylglycerol (DAG) and inositol 1,4,5 trisphospha te (IP3), which in turn activates protein kinase C (PKC) and mobilizes the intracellular Ca2+, respectively. Neutrophils activation of phospholipase D (PLD) and superoxide generation in response to IL-8 have also been demonst rated. Furthermore, IL-8-mediated activation of mitogen activating protein kinase (MAPK) and tyrosine phosphorylation of cellular proteins have been o bserved. it appears that the signalling pathways induced by IL-8 are subjec t to fine modulations by the demand and presence of IL-8. The presence of I L-8 in various pathophysiological condition implies that blockade of its ac tions could be exploited for therapeutic purposes.