Eosinophils are potent pro inflammatory cells involved in the pathogenesis of several human disorders such as asthma and chronic parasitic infections (1
). A better understanding and treatment of these diseases involves elucidating the mechanisms that regulate the selective accumulation of eosinophils. The generation of tissue eosinophilia involves multiple processes, including eosinophil hematopoietic development, endothelial adhesion, chemotaxis, and survival. Whereas eosinophil growth factors, such as IL-5, are involved in eosinophil hematopoiesis and survival, adhesion and locomotion are predominantly controlled by chemoattractants.
The chemokines are a super family of chemotactic cytokines that mediate leukocyte trafficking by binding to specific G protein linked seven transmembrane spanning receptors (2
). Recently, chemokine receptors have been identified as coreceptors for HIV entry into cells and chemokines have been shown to be inhibitors of HIV replication (3
). Chemokines are divided into three groups based on the primary sequence of the first two cysteines: the C–X–C, C–C, and C families. Whereas the C–X–C and C families are mainly active towards neutrophils and lymphocytes, respectively, the C–C family members are active towards macrophages, lymphocytes, basophils, and eosinophils. The eosinophil active chemokines include RANTES, macrophage chemotactic protein (MCP)-2, MCP-3, MCP-4, macrophage inflammatory protein (MIP)-1α, and eotaxin (4
). Eotaxin is the chief eosinophil chemotactic activity released into the lung in a guinea pig model of eosinophilic airway hypersensitivity (5
) and its mRNA is induced in multiple animal models of eosinophilic inflammation and in human tissue in response to allergen challenge (6
). When eotaxin is delivered to experimental animals in vivo, it induces a potent and rapid eosinophil-specific recruitment that is augmented by IL-5 (13
). However, eotaxin may have other activities given that its mRNA is constitutively expressed at high levels in multiple tissues in the absence of eosinophilic inflammation (6
), it has weak macrophage chemoattractive activity at high doses in vitro (8
), its receptor is expressed at low levels in other activated leukocytes (15
), and eotaxin can inhibit the replication of certain HIV strains in vitro (16
). However, the role of eotaxin during eosinophil-mediated disease states is not known. If the activity of eotaxin is indeed restricted to eosinophils, then interference with its function would have clinical utility provided that the other chemoattractants do not have redundant activity. Using a gene disruption strategy, two other chemokines have been demonstrated to have nonredundant roles: MIP-1α in the pathogenesis of viral induced inflammation (17
) and stromal cell–derived factor-1 in B cell lymphopoiesis and myelopoiesis (18
). To explore further the function of eotaxin, we have used gene targeting to create mice with a genetic deficiency in eotaxin.