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The Journal of Immunology, 2002, 168: 5699-5708.
Copyright © 2002 by The American Association of Immunologists

A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12R{beta}1 and a Novel Cytokine Receptor Subunit, IL-23R1

Christi Parham2,3,*, Madaline Chirica2,*, Jacqueline Timans{dagger}, Elena Vaisberg*, Marilyn Travis*, Jeanne Cheung*, Stefan Pflanz{dagger}, Rebecca Zhang{dagger}, Komal P. Singh*, Felix Vega{dagger}, Wayne To{dagger}, Janet Wagner{dagger}, Anne-Marie O’Farrell4,*, Terrill McClanahan{ddagger}, Sandra Zurawski{dagger}, Charles Hannum{dagger}, Daniel Gorman{dagger}, Donna M. Rennick*, Robert A. Kastelein{dagger}, Rene de Waal Malefyt* and Kevin W. Moore5,*

Departments of * Immunology, {dagger} Molecular Biology, and {ddagger} Molecular Pathology, DNAX Research, Palo Alto, CA 94304

IL-23 is a heterodimeric cytokine composed of the IL-12p40 "soluble receptor" subunit and a novel cytokine-like subunit related to IL-12p35, termed p19. Human and mouse IL-23 exhibit some activities similar to IL-12, but differ in their capacities to stimulate particular populations of memory T cells. Like IL-12, IL-23 binds to the IL-12R subunit IL-12R{beta}1. However, it does not use IL-12R{beta}2. In this study, we identify a novel member of the hemopoietin receptor family as a subunit of the receptor for IL-23, "IL-23R." IL-23R pairs with IL-12R{beta}1 to confer IL-23 responsiveness on cells expressing both subunits. Human IL-23, but not IL-12, exhibits detectable affinity for human IL-23R. Anti-IL-12R{beta}1 and anti-IL-23R Abs block IL-23 responses of an NK cell line and Ba/F3 cells expressing the two receptor chains. IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3. The ability of cells to respond to IL-23 or IL-12 correlates with expression of IL-23R or IL-12R{beta}2, respectively. The human IL-23R gene is on human chromosome 1 within 150 kb of IL-12R{beta}2.




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L. S. Argetsinger, J.-L. K. Kouadio, H. Steen, A. Stensballe, O. N. Jensen, and C. Carter-Su
Autophosphorylation of JAK2 on Tyrosines 221 and 570 Regulates Its Activity
Mol. Cell. Biol., June 1, 2004; 24(11): 4955 - 4967.
[Abstract]