Interleukin-8: a very important chemokine of the human airway epithelium.

IN THE LAST TWO AND A HALF DECADES, there has been an explosion of interest in a group of chemotactic cytokines that have chemotactic activity for leukocytes, now known as chemokines. Indeed, there have been more than 16,000 publications related to chemokines since 1975. The human chemokine families are referred to as CXC, CC, C, and CX3C chemokines. These four closely related polypeptide families behave, in general, as potent chemotactic factors for neutrophils, eosinophils, basophils, monocytes, mast cells, dendritic cells, NK cells, and T and B lymphocytes. Chemokines in their monomeric form have a molecular mass of 7–10 kDa and are characteristically basic heparinbinding proteins, which facilitate binding to cells and matrix components within the lung. The chemokines have in common highly conserved cysteine amino acid residues. The CXC chemokine family has the first two NH2-terminal cysteines separated by a single nonconserved amino acid residue, the CXC cysteine motif, whereas the CC chemokine family has the first two NH2-terminal cysteines in juxtaposition, the CC cysteine motif. The C chemokine lymphotactin has a lone NH2-terminal cysteine amino acid, the C cysteine motif, and the CX3C chemokine fractalkine has the first two NH2-terminal cysteines separated by three nonconserved amino acid residues. Interestingly, CXC chemokine genes are, in general, clustered on human chromosome 4, and the proteins exhibit between 20 and 50% homology on the amino acid level, whereas CC chemokine genes are generally clustered on human chromosome 17, and the proteins exhibit between 28 and 45% homology on the amino acid level. The gene that encodes lymphotactin is located on human chromosome 1, and the gene encoding fractalkine is located on human chromosome 16. Overall, there is 20–40% homology between the members of the four chemokine families. Although there has been tremendous interest in chemokines for their ability to recruit specific subpopulations of leukocytes, it is becoming increasingly clear that the function of these cytokines goes well beyond leukocyte trafficking. For example, chemokines are involved in regulating angiogenesis and have direct stimulatory effects on mesenchymeand parenchyme-derived cells, and some members of the chemokine family can exert direct antimicrobial properties similar to that mediated by human defensins. The varied function/biology of chemokines can be best exemplified in the lung. Despite the tremendous interest in chemokines as a whole, the only chemokine with an interleukin designation is IL-8. According to the new chemokine nomenclature, IL-8 is now referred to as CXCL8 (11). In fact, of the more than 16,000 publications on chemokines in the last two and half decades, nearly 7,000 of these publications have cited IL-8/CXCL8. IL-8/CXCL8 is a member of the CXC chemokine family that is also classified by whether a member contains the threeamino acid sequence of glutamic acid-leucine-arginine (Glu-Leu-Arg, “ELR” motif) that immediately precedes the first cysteine amino acid residue in the primary structure of the protein. The members of the CXC chemokine family that contain this motif are referred to as ELR CXC chemokines and have their primary biological effect in promoting neutrophil recruitment and angiogenesis. The gene for IL-8/CXCL8 is found on human chromosome 4, q12–21 (3, 7), and consists of four exons and three introns (3, 7). The 5 -flanking region of IL-8/CXCL8 contains the usual “CCAAT” and “TATA” box-like structures. In addition, this region has a number of potential binding sites for several nuclear factors (3, 7, 9). The IL-8/CXCL8 promoter region is regulated in a cell-specific fashion requiring a NFB element plus either activator protein (AP)-1 or a C/EBP (NF-IL-6) element under conditions of transcriptional induction with tumor necrosis factor (TNF)or IL-1 (1, 2, 4–6, 8, 10). Although the IL-8/ Address for reprint requests and other correspondence: R. M. Strieter, Dept. of Medicine, Div. of Pulmonary and Critical Care Medicine, Dept. of Pathology and Laboratory Medicine, UCLA, 900 Veteran Ave., 14-154 Warren Hall, Box 711922, Los Angeles, CA 90024-1922 (E-mail: [email protected]). Am J Physiol Lung Cell Mol Physiol 283: L688–L689, 2002; 10.1152/ajplung.00146.2002.