Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma

Abstract

In vitro and in vivo studies, in both animal models and human asthmatics, have implicated IL-4 as an important inflammatory mediator in asthma. In a murine asthma model, we examined the anti-inflammatory activities of soluble IL-4R (sIL-4R). In this model, mice sensitized to OVA by i.p. and intranasal (i.n.) routes are challenged with the allergen by i.n. administration. The OVA challenge elicits an eosinophil infiltration into the lungs, with widespread mucus occlusion of the airways, and results in bronchial hyperreactivity. sIL-4R (0.1–100 μg) was administered by either i.n. or i.p. routes before OVA challenge in OVA-sensitized mice. Both blood and bronchoalveolar lavage fluid levels of sIL-4R were significantly elevated compared with controls by i.n. delivery of 100 μg sIL-4R; i.p. delivery of 100 μg sIL-4R only raised blood levels of sIL-4R. The i.n. administration of 100 μg sIL-4R before allergen challenge significantly reduced late phase pulmonary inflammation, blocking airway eosinophil infiltration, VCAM-1 expression, and mucus hypersecretion. In contrast, i.p. delivery of 100 μg sIL-4R inhibited only the influx of eosinophils into the lungs, but not airway mucus release. Furthermore, sIL-4R treatment by either i.n. or i.p. routes did not reduce airway hyperreactivity in response to methacholine challenge. Thus, elevating airway levels of sIL-4R through the administration of exogenous sIL-4R is effective in blocking the late phase pulmonary inflammation that occurs in this murine allergen-challenge asthma model. These results suggest that sIL-4R may have beneficial anti-inflammatory effects in asthmatic patients.

Inhibition of Airway Inflammation by Amino-Terminally Modified RANTES/CC Chemokine Ligand 5 Analogues Is Not Mediated through CCR3

“…not airway hyperresponsiveness, whereas anti-monocyte chemoattractant protein-1/CCL2 mAbs failed to suppress eosinophilic inflammation, but abrogated airway hyperresponsiveness (48). Interestingly, treatment with soluble IL-4R, as performed with these antagonists before OVA challenge in OVA-immunized mice inhibits mucus hypersecretion and eosinophil influx into the lungs, but not bronchohyperactivity to methacholine following allergen challenge (49). These findings strengthen the concept that blocking migration or activation of Th2 T lymphocytes prevents the successive events, which contribute to the pathogenesis of asthma.…”

A Critical Role for Mouse CXC Chemokine(s) in Pulmonary Neutrophilia During Th Type 1-Dependent Airway Inflammation

“…4). Judging from these results and the fact that soluble IL-4R␣ administration inhibited Th2-induced eosinophilia, both IL-5 and IL-13 might be involved in airway eosinophilia coupled with eotaxin (21,22). In contrast to Th2, the role of Th1 cells in airway inflammation remains unclear.…”

IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses

“…Several in vitro and in vivo studies have demonstrated that the sIL-4R binds IL-4 with high affinity and can function as an antagonist of IL-4 activity, competing with the mIL-4R on target cells for the binding of IL-4 (20,26,27,29,52). The production of sIL-4Ra is reduced in Il21r 2/2 mice, in accordance with reduced membrane-bound IL-4Ra and reduced IL-4 production.…”

“…Proteolytic cleavage releases sIL-4R, containing the extracellular portion of IL-4R, from the transmembrane and intracellular domains that remain cellbound. sIL-4R inhibits the biologic actions of IL-4 in vitro (28) and in vivo (29,52). sIL-4R detected in serum by ELISA on day 10 following immunization with NP-OVA in alum showed a significant decrease in sIL-4R in Il21r 2/2 mice when compared with WT mice (Fig.…”

“…There are two forms of the IL-4: one is membrane bound, and the other is a soluble form (sIL-4R) released by proteolytic cleavage (26,27). sIL-4R inhibits the biologic actions of IL-4 both in vitro and in vivo (28,29). The important collective roles of IL-4 and IL-21 are illustrated by the finding that mice made genetically deficient in both Il4 and Il21r exhibit a significantly more pronounced phenotype than the absence of either molecule alone, characterized by a severely impaired Ab response (16).…”