Interleukin-5-mediated Allergic Airway Inflammation Inhibits the Human Surfactant Protein C Promoter in Transgenic Mice

Abstract

Allergen challenge in the lung of humans and animals is associated with surfactant dysfunction, but the mechanism of this effect has not been established. By using a murine model of asthma we now report the effect of allergen-induced airway inflammation on the expression of transgenes regulated by the human surfactant protein (hSP)-C promoter. The hSP-C 3.7-kilobase pair promoter was used to direct the expression of eotaxin, an eosinophil-selective chemokine, into the lungs of several transgenic lines. As expected, the transgenic mice expressed increased amounts of eotaxin mRNA and protein compared with wild-type mice. Surprisingly, following allergen challenge, there was a marked down-regulation of transgene mRNA in three independent transgenic 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-regulation of the eotaxin transgene, there was no increase in pulmonary eosinophil levels in the transgenic mice above that found in wild-type mice. Analysis of hSP-C transgenic mice with distinct reporter genes and 3-untranslated regions revealed that allergen challenge was directly affecting the hSP-C promoter. We hypothesized that allergeninduced down-regulation of the hSP-C promoter was related to the eosinophilic inflammation. To test this, we blocked eosinophilic inflammation in the lungs by treating mice with neutralizing antiserum against interleukin-5. Interestingly, this treatment also blocked allergeninduced inhibition of the hSP-C promoter. These results establish that allergic airway inflammation is associated with up-regulation of the surfactant proteins primarily involved in immunity, whereas down-regulation 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 inflammation. These results suggest that alterations in surfactant protein levels may contribute to immune and airway dysfunction in asthma.

Enterocyte Expression of the Eotaxin and Interleukin-5 Transgenes Induces Compartmentalized Dysregulation of Eosinophil Trafficking

“…However, the expression of eotaxin is not sufficient for eosinophil trafficking, as exemplified by readily detectable eotaxin in the esophagus despite the absence of eosinophils from this gastrointestinal segment (5). In addition, although eotaxin is an allergen-induced gene product in the lungs and contributes to antigen-induced pulmonary eosinophil recruitment (26,45), we have found that transgenic overexpression of eotaxin in the lung does not promote eosinophil accumulation (6). It was thus critical to generate Fabpi-eotaxin transgenic mice to determine the consequences of eotaxin overexpression in the mucosal tissue where our previous data had suggested a dominant role for this chemokine (45).…”

“…These studies have revealed that eosinophils normally reside in the lamina propria of the stomach and intestine and that their base-line level is regulated by eotaxin, an eosinophilselective chemokine (4,5). However, the constitutive expression of eotaxin is not sufficient for tissue eosinophil trafficking, because some gastrointestinal segments (such as the tongue and esophagus) express eotaxin but are normally devoid of eosinophils and eotaxin-lung transgenic mice do no have elevated levels of pulmonary eosinophils (5,6). This may be explained in part by the cooperation of eotaxin with the eosinophilopoietin interleukin (IL) 1 -5, a cytokine that promotes eosinophil growth, development, survival, and responsiveness to chemoattractants (7,8).…”

Foxa2 regulates alveolarization and goblet cell hyperplasia

“…Mice were treated twice by intraperitoneal injection with 100 µg ovalbumin (OVA, Sigma, grade V) and 1 mg aluminum hydroxide (alum) followed by two intranasal treatments, 3 days apart, with either 50 µg OVA or saline, starting at least 10 days after the second sensitization, as previously described (Mishra et al, 2001). Mice were killed 18 hours after the second intranasal administration.…”

The Eotaxin Chemokines and CCR3 Are Fundamental Regulators of Allergen-Induced Pulmonary Eosinophilia

“…A mouse model of allergic lung disease was established as described previously (36). In brief, mice were sensitized by i.p.…”

“…The murine eotaxin-1 ELISA was used as described previously (36). The murine eotaxin-2 ELISA was a newly developed sandwich-type ELISA with custom and commercial antisera.…”