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A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12Rβ1 and a Novel Cytokine Receptor Subunit, IL-23R

2002; American Association of Immunologists; Volume: 168; Issue: 11 Linguagem: Inglês

10.4049/jimmunol.168.11.5699

1550-6606

Christi Parham, Madaline Chirica, Jacqueline Timans, Elena Vaisberg, Marilyn Travis, Jeanne Cheung, Stefan Pflanz, Rebecca Zhang, Komal Singh, Félix V. Vega, Wayne To, Janet Wagner, Anne-Marie O’Farrell, Terrill K. McClanahan, Sandra Zurawski, Charles Hannum, Daniel M. Gorman, D Rennick, Robert A. Kastelein, René de Waal Malefyt, Kevin W. Moore,

Psoriasis: Treatment and Pathogenesis

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-12Rbeta1. However, it does not use IL-12Rbeta2. 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-12Rbeta1 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-12Rbeta1 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-12Rbeta2, respectively. The human IL-23R gene is on human chromosome 1 within 150 kb of IL-12Rbeta2.