title: Allergic lung inflammation is mediated by soluble tumor necrosis factor (TNF) and attenuated by dominant-negative TNF biologics.
abstract: Tumor Necrosis Factor (TNF) is a pleiotropic cytokine consisting of soluble and transmembrane forms, with distinct roles in inflammation and immunity. TNF is an important factor in allergic airway inflammation. However, the disparate functions of soluble (sol) and transmembrane (tm) TNF in lung pathology are not well understood. Our aim was to assess the activities of solTNF and tmTNF in murine models of allergic airway disease, and to evaluate the efficacy of solTNF-selective inhibition. We used ovalbumin sensitization and challenge of TNF knockout, tmTNF knockin, and wild-type C57BL/6 mice to distinguish differences in airway inflammation and hyperreactivity mediated by solTNF and tmTNF. Functions of solTNF and tmTNF in hyperresponsive, wild-type Balb/c mice were assessed by comparing dominant-negative anti-TNF biologics, which antagonize solTNF yet spare tmTNF, to etanercept, a nonselective inhibitor of both TNF forms. Responses in transgenic C57BL/6 mice demonstrated that solTNF, and not tmTNF, is necessary to drive airway inflammation. In Balb/c mice, dominant-negative TNF biologics administered during immunization decreased the recruitment of eosinophils and lymphocytes into the bronchoalveolar space and lung parenchyma, reduced specific serum IgE, goblet-cell hyperplasia, and eosinophilic inflammation, and suppressed methacholine-induced airway hyperreactivity. Concentrations of IL-5, CCL5/RANTES, CCL11/eotaxin, and CCL17/TARC were also reduced in bronchoalveolar lavage. Dominant-negative TNFs reduced lung eosinophilia, even when given only during antigen challenge. The selective inhibition of soluble TNF suppresses inflammation, hyperreactivity, and remodeling in transgenic and wild-type murine models of allergic airway disease, and may offer safety advantages in therapies that preserve the immunoprotective functions of transmembrane TNF.
authors.affiliation: Laboratory of Molecular Immunology and Embryology, University of Orléans, Orléans, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maillet
authors.forename: Silvia
authors.initials: S
authors.lastname: Schnyder-Candrian
authors.forename: Isabelle
authors.initials: I
authors.lastname: Couillin
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Francois
authors.initials: F
authors.lastname: Erard
authors.forename: René
authors.initials: R
authors.lastname: Moser
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fleury
authors.forename: Akira
authors.initials: A
authors.lastname: Kanda
authors.forename: David
authors.initials: D
authors.lastname: Dombrowicz
authors.forename: David E
authors.initials: DE
authors.lastname: Szymkowski
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000068800:Etanercept; D020397:Goblet Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D007073:Immunoglobulin E / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010047:Ovalbumin; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001688:Biological Products; D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595; D007073:Immunoglobulin E; D010047:Ovalbumin; D000068800:Etanercept