Lymphomagenesis, hydronephrosis, and autoantibodies result from dysregulation of IL-9 and are differentially dependent on Th2 cytokines.
Interleukin-9 is an immunoregulatory cytokine implicated in the development of asthma and allergy. To investigate the role of IL-9 in vivo, we have generated transgenic mice in which IL-9 is expressed from its own promoter. Strikingly, overexpression of IL-9 resulted in premature mortality associated with a complex phenotype characterized by the development of autoantibodies, hydronephrosis, and T cell lymphoma. By intercrossing IL-9 transgenic mice with a panel of Th2 cytokine-deficient mice, we demonstrate that these disorders represent distinct phenotypes that can be dissociated by their differential dependence on Th2 cytokines. Autoantibody production was ablated in IL-9 transgenic animals with a combined absence of IL-4, IL-5, and IL-13, coincident with a reduction in peritoneal B-1 cells. Hydronephrosis arose in 75% of IL-9 transgenic animals and was dependent on the presence of IL-4 and IL-13. In contrast, T cell lymphomas developed independently of the other Th2 cytokines, with the generation of rapidly proliferating CD8(+) or CD4(+)CD8(+) T cell clones that arose in the thymus before infiltrating both lymphoid and nonlymphoid tissues. Our data highlight potentially important new roles for IL-9, through its regulation of downstream Th2 effector cytokines, in autoantibody production and in hydronephrosis.
Lauder
Angus J
AJ
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.
Jolin
Helen E
HE
Smith
Philippa
P
van den Berg
José G
JG
Jones
Alison
A
Wisden
William
W
Smith
Kenneth G C
KG
Dasvarma
Ayan
A
Fallon
Padraic G
PG
McKenzie
Andrew N J
AN
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001323:Autoantibodies / Q000096:biosynthesis*; D016207:Cytokines / Q000502:physiology*; D006869:Hydronephrosis / Q000209:etiology*; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D015848:Interleukin-5 / Q000502:physiology; D016906:Interleukin-9 / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000276:immunology*
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D016207:Cytokines; D018793:Interleukin-13; D015848:Interleukin-5; D016906:Interleukin-9; D015847:Interleukin-4