Alpha 4 integrin-induced cytokine production and eosinophil function.

Abstract

The eosinophil α4 integrin receptor is likely to play an important role in eosinophil adhesion as well as signal transduction. In vitro studies have shown that triggering eosinophil α4 integrin induces GM-CSF and IL-3 release by eosinophils [5]. In vivo studies have shown that the eosinophil α4 integrin acts not only as a firm adhesion receptor, but also as a rolling receptor [68]. Preliminary studies of α4 models of asthma suggest that neutralizing antibodies to α4 inhibit eosinophil migration into the airway in some [52], but not all [1] models of asthma. Neutralizing antibodies to α4 improve airway function in some animal models of asthma in which eosinophil migration is only partially inhibited [1]. This suggests that the α4 antibodies may not only be inhibiting recruitment, but also activation of eosinophils. For example, in a sheep model of allergen-induced asthma, the anti-α4 integrin antibody HP 1/2 blocked late-phase airway changes and post-challenge airway hyperresponsiveness, but did not consistently alter the composition of leukocytes (including eosinophils) recovered by bronchoalveolar lavage is [1]. Because the anti-α-4 integrin antibody was also effective in reducing airway responsiveness following airway (as opposed to intravenous) administration, it may have functioned by inhibiting integrin-mediated cellular activation as opposed to inhibiting integrin-mediated adhesion. It is likely that several adhesion receptors other than VLA-4 are important to the pathogenesis of allergic inflammation. For example, in animal models of asthma, neutralizing antibodies to the adhesion molecules E-selectin [33] and ICAM [79] significantly reduce the airway inflammatory response. Therefore, future studies will determine the clinical utility of targeting α-4 integrin receptors in diseases associated with eosinophilic inflammation.