The receptor for interleukin 5 (IL-5) consists of a cytokine-specific  chain (IL-5R) and a signaling β chain, which is shared with interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). These 3 cytokines can act in eosinophil development and activation in vitro, but gene deletion or antibody blocking of IL-5 largely ablates eosinophilic responses in models of allergic disease or helminth infection. We investigated factors acting in differential IL-5R gene splicing to generate either the membrane-anchored isoform (TM-IL-5R) which associates with the common β chain to allow IL-5 responsiveness, or a secreted, antagonist variant (SOL-IL-5R). In a murine myeloid cell line (FDC-P1), transfected with minigenes allowing expression of either IL-5R variant, IL-5 itself, but not IL-3 or GM-CSF, stimulated a reversible switch toward expression of TM-IL-5R. A switch from predominantly soluble isoform to TM-IL-5R messenger RNA (mRNA) expression was also seen during IL-5-driven eosinophil development from human umbilical cord blood-derived CD34+ cells; this was accompanied by surface expression of IL-5R and acquisition of functional responses to IL-5. IL-3 and GM-CSF also supported eosinophil development and up-regulation of TM-IL-5R mRNA in this system, but this was preceded by expression of IL-5 mRNA and was inhibited by monoclonal antibody to IL-5. These data suggest IL-5-specific signaling, not shared by IL-3 and GM-CSF, leading to a switch toward up-regulation of functional IL-5R and, furthermore, that IL-3 and GM-CSF-driven eosinophil development is dependent on IL-5, providing an explanation for the selective requirement of IL-5 for expansion of the eosinophil lineage.

T helper 2 (Th2)-like cells are thought to play a crucial role in the pathogenesis of atopic asthma. In this study, we attempted to evaluate the in vivo effect of suppressing Th2 cell development on allergen-induced airway changes. Repeated exposure of actively sensitized C57B1/6 mice to aerosolized ovalbumin (OA) causes, in comparison to saline-exposed control animals, synthesis of specific IgE, increase of eosinophils in bronchoalveolar lavage fluid and airway hyperresponsiveness. These effects are not observed in OA-exposed, sensitized IL-4-knockout mice. Likewise, these effects are inhibited in OA-exposed C57B1/6 mice treated with IL-12 during initial antigen exposure. These results suggest that suppressing Th2 cell development in vivo might have profound inhibitory effects on allergen-induced airway changes.

We have developed in C57 Black 6 mice an in vivo model of allergic airway inflammation characterized by the presence of IgE antibodies to an inhaled antigen, peribronchial infiltrates with an increased number of eosinophils, and an increased airway responsiveness to nonantigenic bronchoconstrictor stimuli. In this animal model we have investigated the role of different cytokines in the development of IgE antibodies to inhaled antigen, eosinophilic airway inflammation, and airway hyperresponsiveness. The studies were performed by using knockout mice or by exogenous administration of cytokines or cytokine antagonists. Interleukin-4 (IL-4) knockout mice were unable to develop an allergic eosinophilic airway infiltration and did not produce specific IgE antibodies. Chronic aerosol exposure to antigen also did not induce an increase in airway responsiveness. In studies of wild-type mice, pretreatment with the combination of anti-IL5 and anti-IL-5 receptor antibodies, given in an attempt to fully inhibit the effect of endogenously released IL-5, caused a pronounced inhibition of the antigen-induced airway eosinophilia but did not prevent the increase in airway responsiveness. Treatment with IL-12 during the active immunization prevented airway eosinophilia, production of specific IgE antibodies, and the antigen-induced increase in airway responsiveness. In contrast, administration of IL-12 to actively immunized mice during the aerosol exposure abolished airway eosinophilia and airway hyperresponsiveness without affecting the production of specific IgE.