IL-12 Signaling Pathway

Interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. The heterodimeric cytokines of the IL-12 family consist of an α-chain (p19, p28 or p35) and a β-chain (p40 or Ebi3). The α-chains have a four-helix bundle structure characteristic of the IL-6 superfamily, to which the IL-12 family belongs. In contrast, the β-chains share homology with class I receptor chains for cytokines, such as IL-6Rα. The p40 chain can pair with p35 or p19 to form IL-12 or IL-23, respectively, whereas Ebi3 can pair with p28 or p35 to form IL-27 or IL-35, respectively.

The receptor chains are also used by multiple cytokines. IL-12 signals via IL-12Rβ1 and IL-12Rβ2, whereas IL-23 signals via IL-12Rβ1 and IL-23R. In contrast, IL-27 uses gp130 and IL-27R (WSX-1),whereas IL-35 signals via gp130 and IL-12Rβ2.IL-35 is unusual in that it can also signal via two additional receptor-chain compositions: gp130-gp130 and IL-12Rβ2–lL-12Rβ2 homodimers.

Signaling via all of these receptors is mediated by members of the Jak-STAT family. Jak2 and either Jak1 or Tyk2 seem to mediate phosphorylation of STAT proteins associated with receptors for cytokines of the IL-12 family. IL-12 mediates signaling via p-STAT4, IL-23 mediates signaling via p-STAT3 and p-STAT4, IL-27 mediates signaling via p-STAT1 and p-STAT3, and IL-35 mediates signaling via p-STAT1 and p-STAT4. For IL-35, the formation of a STAT1-STAT4 heterodimer is required for transcription of Ebi3 and Il12a but is partially dispensable for the suppression of T cells.