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IL-4 and IL-13 Form a Negative Feedback Circuit with Surfactant Protein-D in the Allergic Airway Response¹

Angela Haczku^2,*, Yang Cao^*, Geza Vass^*, Sonja Kierstein^*, Puneeta Nath, Elena N. Atochina-Vasserman^*, Seth T. Scanlon^*, Lily Li, Don E. Griswold, K. Fan Chung, Francis R. Poulain, Samuel Hawgood^¶, Michael F. Beers^* and Erika C. Crouch^||

^* Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104; National Heart and Lung Institute, London, United Kingdom; Centocor, Malvern, PA 19355; Division of Neonatology, University of California, Davis, CA 95817; ^¶ Division of Neonatology, University of California, San Francisco, CA 94143; and ^|| Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

The innate immune molecule surfactant protein-D (SP-D) plays an important regulatory role in the allergic airway response. In this study, we demonstrate that mice sensitized and challenged with either Aspergillus fumigatus (Af) or OVA have increased SP-D levels in their lung. SP-D mRNA and protein levels in the lung also increased in response to either rIL-4 or rIL-13 treatment. Type II alveolar epithelial cell expression of IL-4Rs in mice sensitized and challenged with Af, and in vitro induction of SP-D mRNA and protein by IL-4 and IL-13, but not IFN-, suggested a direct role of IL-4R-mediated events. The regulatory function of IL-4 and IL-13 was further supported in STAT-6-deficient mice as well as in IL-4/IL-13 double knockout mice that failed to increase SP-D production upon allergen challenge. Interestingly, addition of rSP-D significantly inhibited Af-driven Th2 cell activation in vitro whereas mice lacking SP-D had increased numbers of CD4⁺ cells with elevated IL-13 and thymus- and activation-regulated chemokine levels in the lung and showed exaggerated production of IgE and IgG1 following allergic sensitization. We propose that allergen exposure induces elevation in SP-D protein levels in an IL-4/IL-13-dependent manner, which in turn, prevents further activation of sensitized T cells. This negative feedback regulatory circuit could be essential in protecting the airways from inflammatory damage after allergen inhalation.

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