A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
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.
Parham
Christi
C
Department of Immunology, DNAX Research, Palo Alto, CA 94304, USA.
Chirica
Madaline
M
Timans
Jacqueline
J
Vaisberg
Elena
E
Travis
Marilyn
M
Cheung
Jeanne
J
Pflanz
Stefan
S
Zhang
Rebecca
R
Singh
Komal P
KP
Vega
Felix
F
To
Wayne
W
Wagner
Janet
J
O'Farrell
Anne-Marie
AM
McClanahan
Terrill
T
Zurawski
Sandra
S
Hannum
Charles
C
Gorman
Daniel
D
Rennick
Donna M
DM
Kastelein
Robert A
RA
de Waal Malefyt
Rene
R
Moore
Kevin W
KW
D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018121:Receptors, Cytokine / Q000737:chemistry* / Q000235:genetics; D018123:Receptors, Interleukin / Q000737:chemistry*; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000187:drug effects
C508840:IL23A protein, human; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; C528688:interleukin-23 receptor, mouse; D018664:Interleukin-12