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. 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 an 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.
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.