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

Robert M. Strieter

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Pathology and Laboratory Medicine at the University of California, Los Angeles, School of Medicine, Los Angeles, California 90024-1922


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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 heparin-binding 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 mesenchyme- and 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 three-amino 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 NF-kappa B 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)-alpha or IL-1 (1, 2, 4-6, 8, 10). Although the IL-8/CXCL8 promoter has two C/EBP (5' and 3') cis elements with NF-kappa B nested between them, the 5'-C/EBP element appears to be the only C/EBP element involved in transcriptional regulation of IL-8/CXCL8 (1, 2, 4-6, 8, 10). In specific cell lines, the AP-1 along with NF-kappa B or C/EBP and NF-kappa B cis elements are sufficient for full transcriptional activation of the IL-8/CXCL8 promoter (5, 10). Members of the NF-kappa B/rel and C/EBP families of transcriptional factors can interact on a protein:protein level via the Rel:basic leucine zipper domain of these proteins, respectively (1, 2, 4, 8). Recently, Wu and associates (9) examined the basal transcriptional activity of two epithelial cell lines in which both AP-1 and 5'-C/EBP cis elements bind protein that markedly transactivates the IL-8/CXCL8 promoter in the absence of any agonist stimulation. In addition, they demonstrated that for full transcriptional activation of the promoter there is a cooperative interaction among all three major cis elements (AP-1, 5'-C/EBP, and NF-kappa B).

The promoter region of IL-8/CXCL8 gene has been extensively studied, but the mechanisms related to signal transduction and optimal transactivation of the IL-8/CXCL8 gene have required further elucidation. The study by Li and colleagues, the current article in focus (Ref. 2a, see p. L690 in this issue), uses human airway epithelial cells to show that mitogen-activated protein (MAP) kinases are necessary to optimally induce the gene expression and protein production of IL-8/CXCL8 from these cells in response to TNF-alpha . The investigators demonstrated that TNF-alpha activation of the MAP kinases is able to achieve the induction of IL-8/CXCL8 gene expression and protein production by NF-kappa B -dependent, -independent, and posttranscriptional mechanisms. Using various strategies, they demonstrate that direct inhibition of the MAP kinases (ERK and JNK) and NF-kappa B, but not p38, decreased TNF-alpha -induced transcription of the IL-8/CXCL8 promoter. They found that inhibition of JNK signaling reduced TNF-alpha -induced transcription of the IL-8 promoter in a NF-kappa B-dependent manner, whereas inhibition of ERK impaired TNF-alpha -induced transcription of the IL-8 promoter in a NF-kappa B-independent and AP-1-dependent manner. Finally, they demonstrated that activation of the MAP kinase p38 is important for promoting TNF-alpha -induced IL-8/CXCL8 protein production in a posttranscriptional manner. Although these studies focused on the role of TNF-alpha for the induction of transcription and posttranscriptional production of IL-8/CXCL8, these findings would also be relevant to downstream signal transduction events related to activation of Toll-like receptors and IL-1 type I receptor for the induction of IL-8/CXCL8 gene expression and protein production. Furthermore, the study by Li and associates (2a) highlights the fact that multiple pathways are focused to assure ultimate success in the mediation of IL-8/CXCL8 gene expression and protein production. This scenario is relevant to conditions in which the airway epithelium is needed to respond to pathogen recognition or to react to two of the most important early response cytokines, TNF-alpha and IL-1, in the innate host defense.


    FOOTNOTES

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: rstrieter{at}mednet.ucla.edu).

10.1152/ajplung.00146.2002


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Am J Physiol Lung Cell Mol Physiol 283(4):L688-L689
1040-0605/02 $5.00 Copyright © 2002 the American Physiological Society