title: Enhanced protection from fibrosis and inflammation in the combined absence of IL-13 and IFN-γ.
abstract: Persistent or dysregulated IL-13 responses are key drivers of fibrosis in multiple organ systems, and this identifies this cytokine as an important therapeutic target. Nevertheless, the mechanisms by which IL-13 blockade leads to the amelioration of fibrosis remain unclear. Because IFN-γ exhibits potent anti-fibrotic activity, and IL-4Rα signalling antagonizes IFN-γ effector function, compensatory increases in IFN-γ activity following IL-13/IL-4Rα blockade might contribute to the reduction in fibrosis. To investigate the role of IFN-γ, we developed novel IL-13(-/-) /IFN-γ(-/-) double cytokine-deficient mice and examined disease progression in models of type 2-driven fibrosis. As predicted, we showed that fibrosis in the lung and liver are both highly dependent on IL-13. We also observed increased IFN-γ production and inflammatory activity in the tissues of IL-13-deficient mice. Surprisingly, however, an even greater reduction in fibrosis was observed in IL-13/IFN-γ double deficient mice, most notably in the livers of mice chronically infected with Schistosoma mansoni. The increased protection was associated with marked decreases in Tgfb1, Mmp12, and Timp1 mRNA expression in the tissues; reduced inflammation; and decreased expression of important pro-inflammatory mediators such as TNF-α. Experiments conducted with neutralizing monoclonal antibodies to IL-13 and IFN-γ validated the findings with the genetically deficient mice. Together, these studies demonstrate that the reduction in fibrosis observed when IL-13 signalling is suppressed is not dependent on increased IFN-γ activity. Instead, by reducing compensatory increases in type 1-associated inflammation, therapeutic strategies that block IFN-γ and IL-13 activity simultaneously can confer greater protection from progressive fibrosis than IL-13 blockade alone. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Thirumalai R
authors.initials: TR
authors.lastname: Ramalingam
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gieseck
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Acciani
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: M Hart
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cheever
authors.affiliation: Biomedical Research Institute, Rockville, MD, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Mentink-Kane
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Vannella
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D005260:Female; D006099:Granuloma; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000469:parasitology / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D018793:Interleukin-13; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: collagen; fibroblast; fibrosis; hydroxyproline; interferon; interleukin 13; liver; lung; tumour necrosis factor