The IL-12 family of cytokines includes five members, IL-12, IL-23, IL-27, IL-35, and IL-39, which are alll heterodimeric cytokines consisting of an alpha chain subunit (p19, p28, or p35) paired with a beta chain subunit (p40 or EBI3). Both IL-12 and IL-23 are disulfide-linked dimers consisting of the p40 beta chain linked to either the p35 alpha chain to form IL-12 or p19 alpha chain to form IL-23. In contrast, IL-27, IL-35, and IL-39 contain the Epstein-Barr virus-induced gene 3 (EBI3) beta chain subunit coupled with either p28 to form IL-27, p35 to form IL-35, or p19 to form IL-39.
IL-12 family cytokines signal through heterodimeric receptor complexes and mediate their downstream effects through Jak/STAT signaling pathways. IL-12 signals through a receptor complex consisting of IL-12 R beta 1 and IL-12 R beta 2, while IL-23 signals through a receptor complex consisting of IL-12 R beta 1 and IL-23 R. The other IL-12 family cytokines signal through receptor complexes that contain gp130, a receptor subunit that is shared with the IL-6 family cytokines. gp130 pairs with either IL-27 R alpha/WSX-1 to form the IL-27 receptor complex or with IL-23 R to form the IL-39 receptor complex, while IL-35 has been shown to signal through receptor complexes consisting of either gp130 paired with IL-12 R beta 2, gp130 homodimers, IL-12 R beta 2 homodimers, or IL-12 R beta 2 coupled with IL-27 R alpha/WSX-1. Although IL-12 family cytokines can activate multiple STAT proteins following receptor binding, each cytokine in this family primarily activates one or two STATs that are responsible for mediating their distinct biological effects, which can be either pro- or anti-inflammatory. IL-12 and IL-23 promote inflammation by facilitating either Th1 or Th17 differentiation, respectively. In contrast, both IL-27 and IL-35 act primarily as anti-inflammatory cytokines. IL-39 is a recently discovered cytokine, but research suggests that it stimulates neutrophil differentiation or expansion and thereby is involved in promoting inflammation.