The IL-12 (interleukin 12) family cytokines, including IL-12, IL-23, IL-27 and IL-35, are key players in the regulation of T cell responses. Interleukin-12 (IL-12, IL12) has long been appreciated to play central role in the generation of TH1 cells. Subsequent studies indicated that IL-23 and IL-27, two cytokines that are closely related to IL-12, also regulate TH1-cell responses. IL-12 is composed of p35 and p40 subunits. IL-23 is composed of the IL-12p40 subunit and the IL-23p19 subunit, which shares homology with IL-12p35. IL-27 is composed of EBI3/IL-27B and p28. IL-35, a novel member of IL-12 family, is composed of the IL-12p35 and EBI3 subunits. IL-35 is secreted by regulatory T cells, and suppresses inflammatory responses of immune cells.
Function of the IL-12 family members largely depend on IL-12 family receptors. IL-12 and IL-23 bind to IL-12Rβ1/IL-12Rβ2 and IL-12Rβ1/IL-23R, respectively. IL-12Rβ2 is considered to play a key role in IL-12 function. Upon binding, IL-12Rβ2 becomes tyrosine phosphorylated and provides binding sites for kinases, Tyk2 and Jak2. These are important in activating the JAK-STAT pathway. In regulating the activity of B and T lymphocytes, the effects of IL-27 are eliciting by its interaction with a specific cell surface receptor complex composed of two proteins known as IL-27R and gp130.
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Each IL-12 family member is composed of alpha-subunit with a helical structure similar to type 1 cytokines like IL-6 and a beta-subunit structurally related to the extracellular regions of Type 1 cytokine receptors (e.g. soluble IL-6 receptor).
IL-12 family cytokines are important mediators of immune-mediated inflammatory diseases such as psoriasis, multiple sclerosis, rheumatoid arthritis, and Crohn's disease.
IL-12 family receptors exert their funcitons by binding to their heterodimeric IL-12 family cytokines which can often act synergistically to promote Th1 responses and interferon-γ (IFN-γ) production by T cells.
IL-12 family cytokines mediate their biological activities by binding Janus kinases (JAKs) associated heterodimeric receptors and activating JAK-STAT signaling pathways.
The IL-12 family receptor chains are 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.