title: TNF superfamily member 13, APRIL, inhibits allergic lung inflammation.
abstract: The T-cell functions of a proliferation-inducing ligand (APRIL, also known as TNFSF13) remain largely undefined. We previously showed that APRIL suppressed Th2 cytokine production in cultured CD4(+) T cells and Th2 antibody responses. Here we show that APRIL suppresses allergic lung inflammation, which is associated with diminished expression of the transcription factor c-maf. Mice deficient in the April gene (April(-/-) mice) had significantly aggravated lung inflammation compared with WT mice in the ovalbumin-induced allergic lung inflammation model. Likewise, blockade of APRIL in WT mice by the APRIL-receptor fusion protein, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)-Ig, enhanced lung inflammation. Transfer of APRIL-sufficient, ovalbumin-specific, TCR-transgenic CD4(+) T (OT-II) cells to April(-/-) mice restored the suppressive effect of APRIL on lung inflammation. Mechanistically, the expression of the Th2 cytokine transcription factor c-maf, but not GATA-3, was markedly enhanced in April(-/-) CD4(+) T cells at the RNA and protein level and under non-polarizing (Th neutral, ThN) and Th2-polarizing conditions. Since c-maf transactivates the IL-4 gene, the increased c-maf expression in April(-/-) mice readily explains increased Th2 cytokine production. Independent of its effect on IL-4, APRIL suppressed IL-13 expression. APRIL thus may regulate lung inflammation in a dual way, by acting on c-maf expression and by directly controlling IL-13 production.
authors.affiliation: Department of Microbiology & Immunology, University of Miami, Leonard Miller School of Medicine, Miami, FL, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xiao
authors.forename: Seiichi
authors.initials: S
authors.lastname: Motomura
authors.forename: Vadim
authors.initials: V
authors.lastname: Deyev
authors.forename: Eckhard R
authors.initials: ER
authors.lastname: Podack
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000276:immunology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D051257:Proto-Oncogene Proteins c-maf / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000276:immunology*
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D018793:Interleukin-13; C495608:Maf protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D011993:Recombinant Fusion Proteins; C486361:Tnfrsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D015847:Interleukin-4