TNF superfamily member 13, APRIL, inhibits allergic lung inflammation

Eur J Immunol. 2011 Jan;41(1):164-71. doi: 10.1002/eji.201040436. Epub 2010 Dec 1.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Asthma / immunology*
  • Asthma / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • GATA3 Transcription Factor / immunology
  • Interleukin-13 / biosynthesis
  • Interleukin-13 / immunology
  • Interleukin-4 / immunology
  • Lung / immunology*
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Pneumonia / immunology*
  • Pneumonia / pathology
  • Proto-Oncogene Proteins c-maf / immunology
  • Recombinant Fusion Proteins / immunology
  • Th2 Cells / immunology
  • Transmembrane Activator and CAML Interactor Protein / immunology
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / immunology*


  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Interleukin-13
  • Maf protein, mouse
  • Proto-Oncogene Proteins c-maf
  • Recombinant Fusion Proteins
  • Tnfrsf13b protein, mouse
  • Transmembrane Activator and CAML Interactor Protein
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Interleukin-4