Eotaxin. An essential mediator of eosinophil trafficking into mucosal tissues.

Eosinophil accumulation in the peripheral blood and tissues is a hallmark feature of several important medical diseases, including atopic disorders (allergic rhinitis, asthma, and eczema), parasitic infections, and numerous systemic diseases (e.g., Churg Strauss syndrome, eosinophilic pneumonia, eosinophilic gastroenteritis, and the idiopathic hypereosinophilic syndrome) (1). The findings that eosinophils normally account for only a small percent of circulating or tissue-dwelling cells and that their numbers markedly and selectively increase under specific disease states indicate the existence of molecular mechanisms that regulate the selective generation and accumulation of these leukocytes. The pathologic role of eosinophils primarily occurs in tissues; therefore, a major focus of scientific investigation on eosinophils has been to elucidate the processes involved in eosinophil tissue recruitment. Numerous mediators have been identified as eosinophil chemoattractants, including diverse molecules, such as lipid mediators (platelet-activating factor, leukotrienes), bacterial products (formylmethionyl leucylphenylalanine [FMLP]), and recently, chemokines such as RANTES (regulated on activation, normal T cells expressed and secreted) and macrophage inflammatory protein (MIP)-1 a (2). However, none of these mediators selectively promote eosinophil recruitment; they are therefore not considered to be the primary mediators of the tissue eosinophilia observed in numerous hypereosinophilic disorders. In contrast to these molecules, eotaxin is an eosinophilselective chemoattractant and therefore has been the subject of recent intensive research. Eotaxin was initially discovered using a biologic assay in guinea pigs designed to identify the molecules responsible for allergen-induced eosinophil accumulation in the lungs. Using an in vivo chemotaxis assay in guinea-pig skin, the partial amino acid sequence for the protein responsible for eosinophil chemoattraction in the bronchoalveolar fluid in allergen-challenged guinea pigs was determined (3). This facilitated the genetic cloning of the genes and complemenatry DNA (cDNA) for guinea pig, murine, and human eotaxin, and the identification of eotaxin as a member of the CC chemokine family most homologous to the macrophage chemoattractant protein (MCP) subfamily (4–7). This subfamily of eotaxin and MCP chemokines is clustered on human chromosome 17q11, a region clustered with other CC chemokines (such as MIP-1, I-309, RANTES, and HCC-1, -2) (8). Interestingly, this region has been recently linked to asthma susceptibility (9). Recently, another chemokine, which is active primarily on eosinophils, has been identified, and this chemokine has been termed eotaxin-2 (10). Eotaxin-2 is only distantly related to eotaxin because it is only 39% homologous and is located in a different chromosomal position (7q11). The cloning of these genes and the production of recombinant protein enabled the biologic activity of eotaxin to be examined. Eotaxin was distinguished from all other chemokines because it was found to be a potent eosinophil-selective chemoattractant having minimal activity on other leukocytes. Eotaxin was also identified as a potent activator of eosinophils capable of inducing superoxide generation and the release of granule proteins. Eotaxin was subsequently shown to also be active on human peripheral blood basophils, stimulating chemoattraction in vitro and weak histamine release from IL-3–primed basophils (11). Administration of eotaxin in vivo has been performed in guinea pigs, rodents, and primates, and all of these studies have consistently demonstrated a strong preference of eotaxin for eosinophils in vivo because the eosinophil is the only cell that is recruited. Interestingly, the activity of eotaxin in vivo is enhanced by the copresence of interleukin (IL)-5 (12). IL-5, an eosinophil-selective hematopoietin that regulates eosinophil growth, differentiation, and survival, is a potent stimulus for the release of eosinophils and eosinophil precursors from the bone marrow into the peripheral circulation (13). The increased level of circulating eosinophils and the ability of IL-5 to prime eosinophils to have enhanced responsiveness to eotaxin probably accounts for the synergy between these two cytokines (14). The specific activity of eotaxin is mediated by the selective expression of the eotaxin receptor, CC chemokine receptor-3 (CCR-3), a seven-transmembrane–spanning G-protein–linked genetically polymorphic receptor primarily ex( Received in original form July 1, 1999 )