CD4+ T cell-dependent airway mucus production occurs in response to IL-5 expression in lung

1 Divisions of Hematology/Oncology and 2 Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259; and 3 Pharmaceutical Division, Department of Biotechnology, Bayer Corporation, Berkeley, California 94701-1986 The potential role of airway interleukin-5 (IL-5) expression in eliciting mucus production was demonstrated in a pulmonary IL-5 transgenic mouse model (NJ.1726) in which naive transgenic mice display comparable levels of airway mucus relative to allergen-sensitized and -challenged wild-type mice. The intrinsic mucus accumulation of NJ.1726 was abolished in compound transgenic-gene knockout mice deficient of either CD4 + cells [NJ.1726/CD4( / )] or T cell receptor-positive (TCR + ) cells [NJ.1726/ TCR( / )]. In addition, mucus production in naive NJ.1726 was inhibited by >90% after administration of the soluble anti-IL-4 receptor -subunit antagonist. The loss of mucus production in NJ.1726/CD4( / ), NJ.1726/ TCR( / ), and anti-IL-4 receptor -subunit antagonist-treated mice occurred notwithstanding the significant pulmonary eosinophilia and expansion of airway B cells induced by ectopic IL-5 expression. Furthermore, the loss of mucus accumulation occurred in these mice despite elevated levels of airway and peripheral IL-5, indicating that IL-5 does not directly induce goblet cell metaplasia and mucus production. Thus pulmonary expression of IL-5 alone is capable of inducing CD4 + T cell-dependent goblet cell metaplasia, apparently mediated by IL-4 receptor -subunit-ligand interactions, and represents a previously unrecognized novel pathway for augmenting allergen-induced mucus production. asthma; goblet cell; transgenic; gene knockout