Nicholas W. Lukacs1, Allison L. Miller and Cory M. Hogaboam
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
The overall incidence, severity, and prevalence of asthma has risen dramatically with a distressing increase in children (1). Asthmatics are presently treated with nonspecific inhibitors of the inflammatory responses using inhaled or oral steroids accompanied by bronchodilating reagents but the overall long-term success of these treatments is debated. Although there are several contributing factors that promote severe asthmatic responses, it appears that peribronchial inflammation is a common underlying factor. There is substantial evidence that allergic inflammatory responses are driven by Th2-type cytokines including IL-4, IL-5, and IL-13 (2). The sources for the cytokines include lymphocytes, mast cells, and eosinophils, all of which participate in the allergic asthmatic responses. The mechanism governing the preferential recruitment and activation of these participating cells has been a primary focus directed at discovering therapeutic strategies. A group of cytokines that have prominent effects on leukocyte recruitment and activation are the chemokines. A common conception among researchers to date has been that blocking the correct chemokine or chemokine receptor should significantly attenuate the accumulation and/or activation of leukocyte populations that drive the asthmatic response. Although much of the data have been derived from animal models of asthma, several aspects appear to be promising for attenuating disease.
Chemokines have been traditionally divided into two main groups based upon their sequence homology and the position of the first two cysteine residues, C-X-C ( ) and C-C ( ). Presently there are 16 CXC ligands (CXCL1-16) and 28 CC ligands (CCL1-28) that have been identified. There are also two minor groups, the CX3C and C, both having only a single identified member. Many of the chemokines originally had multiple names that were assigned to these molecules; however, consensus within the field has standardized their nomenclature (3). These chemokine ligands bind to G protein-coupled 7 transmembrane serpentine receptors, but the function and cellular expression patterns still require classification. There are six known CXC chemokine receptors, 10 known functional CC chemokine receptors, and at least two known receptors that do not signal (DARC and D6) but are able to bind to CC and CXC chemokines possibly acting as decoy receptors. The complexity of understanding chemokine biology comes from the promiscuous binding of a single chemokine to multiple receptors, while individual receptors can bind multiplechemokines. Chemokines have diverse functions during asthmatic responses, which relate to recruitment, cellular activation/degranulation, differentiation, as well as directly altering the immune response (4). The identification of chemokines in the airways of asthmatics after allergen provocation initially suggested that these molecules might have a significant role in the accumulation of leukocytes (5). Furthermore, the expression of distinct chemokine receptors on infiltrating cell populations, especially lymphocytes and eosinophils, provides an attractive opportunity to attenuate the influx of these cell populations.