Interleukin-5-mediated allergic airway inflammation inhibits the human surfactant protein C promoter in transgenic mice

Allergen challenge in the lung of humans and animals is associated with sur factant dysfunction, but the mechanism of this effect has not been establis hed. By using a murine model of asthma we now report the effect of allergen -induced airway inflammation on the expression of transgenes regulated by t he human surfactant protein (hSP)-C promoter. The hSP-C 3.7-kilobase pair p romoter was used to direct the expression of eotaxin, an eosinophil-selecti ve chemokine, into the lungs of several transgenic lines. As expected, the transgenic mice expressed increased amounts of eotaxin mRNA and protein com pared with wild-type mice. Surprisingly, following allergen challenge, ther e was a marked down-regulation of transgene mRNA in three independent trans genic lines. The down-regulation was in contrast to other related proteins such as endogenous eotaxin and surfactant protein D levels, which were both increased following allergen challenge. Consistent with specific down-regu lation of the eotaxin transgene, there was no increase in pulmonary eosinop hil levels in the transgenic mice above that found in wild-type mice. Analy sis of hSP-C transgenic mice with distinct reporter genes and S'-untranslat ed regions revealed that allergen challenge was directly affecting the hSP- C promoter. We hypothesized that allergen induced down-regulation of the hS P-C promoter was related to the eosinophilic inflammation. To test this, we blocked eosinophilic inflammation in the lungs by treating mice with neutr alizing antiserum against interleukin-5, interestingly, this treatment also blocked allergen-induced inhibition of the hSP-C promoter. These results e stablish that allergic airway inflammation is associated with up-regulation of the surfactant proteins primarily involved in immunity, whereas down-re gulation of the surfactant protein primarily involved in maintaining airway patency. Furthermore, the marked down-regulation of the hSP-C promoter is interleukin-5-dependent, implying a critical role for eosinophilic inflamma tion. These results suggest that alterations in surfactant protein levels m ay contribute to immune and airway dysfunction in asthma.