Chemokines active on eosinophils: potential roles in allergic inflammation

p resendy, the eosinophil is recognized as a proinflammatory granulocyte imphcated in protection against parasitic infection and hkely plays a major rote in allergic diseases, such as bronchial asthma, allergic rhinitis, and atopic dermatitis (1). The eosinophil is a rich source of cytotoxic proteins, hpid mediators, oxygen metabohtes, and cytokines: all with the potential to induce pathophysiology (2). Numerous studies have shown striking eosinophil infiltration into tissues in disease. For example, even in mild asthma (3) eosinophil and lymphocyte infiltration in respiratory epithelium is a consistent finding. Correlations exist between the number of infiltrating eosinophils and disease severity in asthma (3). Pulmonary segmental allergen challenge in sensitive individuals causes eosinophil recruitment into the airways associated with release of biologically active granule proteins and increases in vascular permeabihty (4, 5). Marked eosinophil infiltration and deposition of granule proteins are found in areas ofepithehal desquamation in paranasaI sinus tissues in patients with chronic sinusitis (6). Deposition of eosinophil granule proteins is also prominent in pruritic and eczematous lesions of patients with atopic dermatitis (7). In contrast, infiltration of neutrophils is not prominent in chronic allergic inflammation (8, 9). Yet, in spite of numerous studies (10), the mechanisms allowing selective infiltration of eosinophils in allergic diseases have been a mystery for more than two decades (11). Several mechanisms for selective eosinophil infiltration in disease are known. The migration ofleukocytes through the endothehum involves sequential steps in which the cells are initially hghtly tethered to the endothehum and roll along its surface. Locally released mediators, some of which may be attached to proteoglycans on the endothelial surface, activate leukocytes leading to increased affinity and/or increased expression of cell surface integrins; this permits a firmer bond between the leukocyte and the endothelial cell and results in successful adhesion and transmigration. These general mechanisms of leukocyte infiltration are apphcable to eosinophils and provide opportunities for selective migration. First, eosinophils but not neutrophils express the [31 integrin ct4131 [very late antigen (VLA-4)], and the [37 integrin, 0t4137, and VLA-4 binds to the vascular cell adhesion molecule (VCAM)-I on endothehal cells. This adhesion pathway may permit selective migration of eosinophils (12). VCAM-1 on endothelial cells is upregulated by IL-4 and IL-13, important cytokines in allergic inflammation, and increased expression of these cytokines may further enhance eosinophil recruitment (13). This hypothesis is supported by the observation that eosinophil, but not neutrophil, adhesion and transmigration through monolayers of human umbilical vein endothelial cells (HUVEC) is enhanced by IL-4 (14) and by findings that antibodies to VLA-4 block eosinophil infiltration in guinea pigs (15, 16). However, the expression of VCAM-1 in human allergic inflammation is relatively modest compared to the other adhesion molecules, such as selectins and intercellular adhesion molecule (ICAM)-I (17), raising doubts about the importance of this mechanism for selective eosinophil infiltration in disease. Second, among the eosinophil growth factors, IL-5 possesses chemokinetic and chemotactic activities for eosinophils, but not for other leukocytes (18). Although IL-5 is a relatively weak chemoattractant, it effectively and specifically primes eosinophils for enhanced chemotactic responsiveness to suboptimal concentrations of platelet-activating factor (PAF) and leukotriene B 4 (LTB4) (19). Thus, a highly effective but nonspecific mediator, such as PAF (20), could combine with a highly selective but weakly chemotactic agent, such as IL-5, to promote the specific eosinophil accumulation. Evidence for the importance of IL-5 in eosinophil-associated inflammation abounds. IL-5 is the predominant eosinophil-active cytokine in the allergen-induced pulmonary late-phase allergic reaction (21). Antibodies against IL-5 prevent both eosinophil migration into the lungs and airway hyperreactivity in allergen-challenged monkeys and guinea pigs (22, 23). Mice rendered IL-5 deficient by homologous gene recombination fail to develop eosinophil infiltration into the lungs, airway hyperresponsiveness, and lung damage in a model of asthma (24). In contrast, mice transgenic for human IL-5 have extremely high numbers of circulating eosinophils yet show no pathology nor organ localization (25), thus pointing to the critical importance of local IL-5 production. Finally, both IL-2 (26) and IL-16 (lymphocyte chemoattractant factor) (27) are exceedingly potent chemoattractants for eosinophils. However, in spite of the potency and specificity of these chemoattractants their roles in the induction of eosinophil tissue infiltration remain obscure. An exciting development in the area of eosinophil biology has been the identification of chemotactic cytokines termed "chemokines." The chemokines have four conserved cysteine residues that form characteristic disulfide bonds and