Click on one of the IL-12 family cytokines below to see a list of select ligand-producing cells, major target cells, and the primary biological effects induced by each cytokine.
The IL-12 family of heterodimeric cytokines includes IL-12, IL-23, IL-27, and IL-35. The first three of these cytokines are produced primarily by dendritic cells, macrophages, and monocytes, while IL-35 is produced by regulatory T and regulatory B cells. Each of the IL-12 family cytokines consists of two subunits: an alpha chain (p19, p28, or p35) with a four alpha-helix bundle structure and a beta chain (p40 or EBI3) that is homologous to the soluble class I cytokine receptor chains. The alpha and beta chain subunits are shared among different members of the IL-12 family. IL-12 is composed of the p35 alpha chain and the p40 beta chain, which are covalently linked by a disulfide bond to form the IL-12 p70 protein. IL-23 also contains the IL-12 p40 subunit, but in this case, it is disulfide-linked to a unique p19 alpha chain that shares homology with IL-12 p35. Similarly, both IL-27 and IL-35 consist in part of a shared IL-12/IL-23 p40-related protein known as Epstein-Barr virus-induced gene 3 (EBI3). EBI3 pairs with either p28, a polypeptide related to IL-12 p35, to form IL-27 or with the p35 subunit of IL-12 to form IL-35.
Due to similarities in the subunit composition of the IL-12 family cytokines, many of the receptors for these cytokines also have common chains and activate seemingly comparable downstream signaling pathways. IL-12 and IL-23 both signal through heterodimeric receptor complexes that contain IL-12 R beta 1 paired with either IL-12 R beta 2 for the IL-12 receptor or with IL-23 R for the IL-23 receptor. Likewise, the receptor complexes for IL-27 and IL-35 both contain gp130, a common receptor subunit shared by the IL-6 family cytokines. gp130 couples with IL-27 R alpha/WSX-1 to form the IL-27 receptor complex, while it pairs with IL-12 R beta 2 to form the IL-35 receptor complex in T cells. Additionally, homodimers of gp130 or IL-12 R beta 2 have also been shown to elicit a partial IL-35-induced response in T cells, while in B cells, IL-35 has been shown to signal through a receptor complex comprised of IL-12 R beta 2 and IL-27 R alpha/WSX-1. Following receptor binding, all members of the IL-12 family trigger the activation of Jak2 along with Tyk2 and/or Jak1, leading to the phosphorylation of a subset of STAT proteins, which then homodimerize or heterodimerize and translocate to the nucleus where they induce the expression of target genes. Although multiple STAT proteins may be activated by each IL-12 family cytokine, typically the biological effects associated with different cytokines have been attributed to the activities of one or two STAT proteins. The primary STATs required for signaling by each IL-12 family cytokine are shown as the larger, more brightly colored STAT molecules in the cytokine-specific signaling pathways presented in the graphic (refer to the key at the bottom of the pathway).
Despite similarities in the signaling pathways that they activate, cytokines belonging to the IL-12 family have distinct effects on the immune response. A number of these effects are brought about by the ability of the IL-12 family cytokines to differentially regulate the activities of specific T cell subsets. Signaling induced by IL-12 promotes the differentiation of naïve CD4+ T cells into Th1 cells, induces proliferation and IFN-gamma production by natural killer (NK) cells and T cells, and enhances the cytotoxicity of NK cells and cytotoxic T lymphocytes. In contrast, IL-23 signaling is involved in the stabilization and maintenance of Th17 cells, promotes memory T cell activation, and stimulates IL-17-mediated neutrophil recruitment to sites of infection. Although these activities demonstrate that IL-12 and IL-23 induce different immune responses, both can be characterized as pro-inflammatory.
IL-27 is unique in that it has both pro- and anti-inflammatory effects. IL-27 drives inflammation by promoting the early commitment of naïve CD4+ T cells to a Th1-specific lineage through the induction of T-bet, but it also suppresses inflammation by inhibiting Th17 differentiation and inducing the conversion of effector T cells into IL-10-producing T regulatory type I-like (Tr1-like) cells. This functional dichotomy suggests that IL-27 may play a critical role in regulating the delicate balance between pro- and anti-inflammatory signaling. Unlike other IL-12 family members, IL-35 seems to function solely as an anti-inflammatory cytokine. It enhances regulatory T cell proliferation, suppresses the proliferation of conventional T cells, and induces the conversion of naïve conventional T cells into IL-35-producing induced regulatory T cells (iTr35 cells). In addition, IL-35 promotes the conversion of B cells into IL-10-, IL-35-producing regulatory B cells, suggesting that it may inhibit the pathogenesis of autoimmune and inflammatory diseases.
To learn more, please visit our IL-12 Family Research Area.