Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death.
p19, a molecule structurally related to IL-6, G-CSF, and the p35 subunit of IL-12, is a subunit of the recently discovered cytokine IL-23. Here we show that expression of p19 in multiple tissues of transgenic mice induced a striking phenotype characterized by runting, systemic inflammation, infertility, and death before 3 mo of age. Founder animals had infiltrates of lymphocytes and macrophages in skin, lung, liver, pancreas, and the digestive tract and were anemic. The serum concentrations of the proinflammatory cytokines TNF-alpha and IL-1 were elevated, and the number of circulating neutrophils was increased. In addition, ubiquitous expression of p19 resulted in constitutive expression of acute phase proteins in the liver. Surprisingly, liver-specific expression of p19 failed to reproduce any of these abnormalities, suggesting specific requirements for production of biologically active p19. Bone marrow transfer experiments showed that expression of p19 by hemopoietic cells alone recapitulated the phenotype induced by its widespread expression, pointing to hemopoietic cells as the source of biologically active p19. These findings indicate that p19 shares biological properties with IL-6, IL-12, and G-CSF and that cell-specific expression is required for its biological activity.
Wiekowski
M T
MT
Department of Immunology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Leach
M W
MW
Evans
E W
EW
Sullivan
L
L
Chen
S C
SC
Vassileva
G
G
Bazan
J F
JF
Gorman
D M
DM
Kastelein
R A
RA
Narula
S
S
Lira
S A
SA
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D000740:Anemia / Q000097:blood / Q000235:genetics / Q000276:immunology; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D002645:Chickens; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D006130:Growth Disorders / Q000235:genetics* / Q000276:immunology / Q000401:mortality*; D006411:Hematopoiesis, Extramedullary / Q000235:genetics / Q000276:immunology; D006801:Humans; D007246:Infertility / Q000235:genetics* / Q000276:immunology / Q000401:mortality*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000401:mortality; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics*; D007958:Leukocyte Count; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009504:Neutrophils / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D011817:Rabbits; D019076:Transgenes / Q000276:immunology*
D000209:Acute-Phase Proteins; D016207:Cytokines; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; D007378:Interleukins; D007334:Insulin-Like Growth Factor I