The role of interleukin-8 and its receptors in inflammatory lung disease: implications for therapy

Abstract

Neutrophils have been implicated in the pathogenesis of many inflammatory lung diseases, including the acute respiratory distress syndrome, chronic obstructive pulmonary disease and asthma. The CXC chemokine interleukin (IL)-8, is a potent neutrophil recruiting and activating factor and the detection of IL-8 in clinical samples from patients with these diseases has led clinicians to believe that antagonism of IL-8 may be a practicable therapeutic strategy for disease management. Work over the last decade has concentrated on both the molecular mechanisms by which IL-8 is produced in the inflammatory setting and also on the manner in which IL-8 activates the neutrophil. Expression of the IL-8 gene appears to be controlled by several components of the inflammatory milieu. Whilst lipopolysaccharide, IL-1beta and tumor necrosis factor-alpha are capable of augmenting IL-8 production, IL-10 is a potent inhibitor of IL-8 synthesis and appears to play an auto-regulatory role. Regulation of the IL-8 gene is under the control of nuclear factor kappaB which appears to be a primary target for corticosteroid-mediated repression of IL-8 production. IL-8 exerts is effects on neutrophils by binding with high affinity to two receptors on its cell surface, the chemokine receptors CXCR1 and CXCR2. These closely related receptors belong to the superfamily of G-protein coupled receptors, proteins that historically have proved amenable to antagonism by small molecules. The recent descriptions in the literature of highly potent small molecule antagonists of CXCR2 and their success in blocking in vivo trafficking of neutrophils suggest that antagonism of IL-8 at the receptor level is a viable therapeutic strategy. Clinical trials of such compounds will ultimately provide crucial information currently lacking and will define whether or not IL-8 blockade provides future therapy in pulmonary disease.

Fig. 1

(a) represents the primary sequence of the mature interleukin (IL)-8 protein. Conserved cysteine residues are underlined. The location of the first, second and third β-pleated sheets and the α helix within the sequence are indicated overhead, (b) illustrates the solution structure of monomeric IL-8 as deduced by Clore et al.[5] and was produced by the package SwissPdb Viewer v3.51 [6] (URL: http://www.expasy.ch/spdbv/) using the file PDB ID: 1IL8 deposited in the protein data bank[7] (URL: http://www.rcsb.org/pdb/).

Fig. 2

The promiscuity of CXCR2 compared with CXCR1. Both receptors couple to intracellular pathways leading to activation of the neutrophil and a resultant microbicidal response. ENA-78 = epithelial cell-derived neutrophil activating peptide-78; GCP-2 = granulocyte chemotactic protein-2; GROα = growth-related oncogene-α; IL-8 = interleukin-8.

Fig. 3

The chemical structure of the potent small molecule CXCR2 antagonist SB 225002 as described by White and colleagues.[84]