Interleukin-8: An Autocrine Inflammatory Mediator

Abstract

Tnterleukin-8 (TL-8), a pro-inflammatory chemokine, induces trafficking of neutrophils across the vascular wall. The release of IL-8 is triggered by inflammatory signals from a large variety of cells. The diversity in the cellular source indicates pleiotropy of its functions. TL-8 plays a key role in host defense mechanism through its effects on neutrophil activation, but a continued presence of IL-8 in circulation in response to inflammatory conditions may lead to a variable degree of tissue damage. Like most of the peptide hormones or mediators, TL-8 transmits its signals through distinct cell surface receptors. The membrane spanning heptahelical TL-8 receptor is coupled with the effector enzyme(s) through the intermediacy of heterotrimeric OTP-binding regulatory proteins. A growing number of studies demonstrated regulation of IL-8 activity by pertussis toxin treatment, implying a role of pertussis toxin sensitive G proteins (Gi), in TL-8 induced effects. TL-8 induced activation of G-protein results in activation of phospholipase C 2 (PLC 2). This enzyme catalyzes the hydrolysis of membrane phosphoinositides to yield diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (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 demonstrated. Furthermore, TL-8-mediated activation of mitogen activating protein kinase (MAPK) and tyrosine phosphorylation of cellular proteins have been observed. It appears that the signalling pathways induced by TL-8 are subject to fine modulations by the demand and presence of IL-8. The presence of IL-8 in various pathophysiological condition implies that blockade of its actions could be exploited for therapeutic purposes.