title: IL-4 and IL-13 form a negative feedback circuit with surfactant protein-D in the allergic airway response.
abstract: 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-gamma, 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.
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. haczku@mail.med.upenn.edu
authors.forename: Angela
authors.initials: A
authors.lastname: Haczku
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Geza
authors.initials: G
authors.lastname: Vass
authors.forename: Sonja
authors.initials: S
authors.lastname: Kierstein
authors.forename: Puneeta
authors.initials: P
authors.lastname: Nath
authors.forename: Elena N
authors.initials: EN
authors.lastname: Atochina-Vasserman
authors.forename: Seth T
authors.initials: ST
authors.lastname: Scanlon
authors.forename: Lily
authors.initials: L
authors.lastname: Li
authors.forename: Don E
authors.initials: DE
authors.lastname: Griswold
authors.forename: K Fan
authors.initials: KF
authors.lastname: Chung
authors.forename: Francis R
authors.initials: FR
authors.lastname: Poulain
authors.forename: Samuel
authors.initials: S
authors.lastname: Hawgood
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
authors.forename: Erika C
authors.initials: EC
authors.lastname: Crouch
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001988:Bronchiolitis / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism*; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D018793:Interleukin-13 / Q000378:metabolism / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology
chemical_list: D000485:Allergens; D017252:CD3 Complex; C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; D019742:Chemokines, CC; D018793:Interleukin-13; D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma