IL-4 induces production of the lung collectin surfactant protein-D

Background: Surfactant protein (SP)-D is an epithelial cell product of the distal air spaces that aids uptake and clearance of inhaled pathogens and allergens. Allergic airway inflammation significantly increases SP-D levels in the bronchoalveolar lavage fluid in asthmatic patients and mouse models, but the mechanisms involved remain unknown. Objective: To investigate the effects of the T(H)2-type cytokine IL-4 on SP-D production by isolated pulmonary epithelial cells. Methods: Rat type II alveolar epithelial cells were purified and cultured with dexamethasone, cAMP, and isobutyl-l-methyl-xanthine (DCI). The effects of IL-4 on SP-D expression were investigated at the protein and mRNA levels by means of Western and Northern blot analyses. Results: In contrast to a lamellar body protein ABCA3 and surfactant protein-A, expression of SP-D significantly declined when cells were cultured in medium alone for 24 hours. The presence of DCI in the culture medium restored SP-D levels, which were enhanced by 2-fold after addition of recombinant IL-4. The enhancing effects of IL-4 were concentration-dependent, with maximum effects observed at 20 ng/mL (1.43 nmol/L). IL-4 did not rescue cycloheximide-induced decrease of intracellular SP-D levels and did not inhibit extracellular release of SP-D. However, IL-4 significantly augmented DCI-induced SP-D mRNA expression by approximately 2.5-fold over control levels. Conclusions: IL-4 selectively upregulates SP-D expression, and it may act at the level of mRNA in isolated pulmonary epithelial cells. Since SP-D has a potent anti-inflammatory function, this mechanism may be part of a negative feedback loop providing a regulatory link between adaptive and innate immunity during allergic inflammation.