Inflame and restrain - the paradoxical roles of IL-12 and IL-23 in immunity

Within the IL-12 superfamily of heterodimeric cytokines, IL-12 and IL-23, which share a subunit, are among the most pro-inflammatory members. Both are primarily produced by phagocytes and have key roles in activating and regulating T lymphocytes, natural killer cells and innate lymphoid cells. IL-12 predominantly promotes type 1 immune responses, whereas IL-23 is closely associated with type 3 immunity. Their receptors are also heterodimeric and, upon engagement, they trigger 'cytokine polarization' (the imprinting of functional identities on immune cells by activating lineage-defining transcription factors), which contributes to inflammation and immunopathology. IL-12 has a key role in various inflammatory conditions and is a potent driver of antitumour immunity, and IL-12 delivery is being explored in several clinical trials in cancer. By contrast, IL-23 is essential for maintaining barrier tissue integrity, yet its dysregulation is a central driver of autoimmune diseases such as psoriasis. Beyond their well-established pro-inflammatory roles, studies of both cytokines have also yielded paradoxical findings. Emerging evidence suggests that both IL-12 and IL-23 can also attenuate immune responses. In this Review, we explore the discovery of IL-12 and IL-23, their canonical pro-inflammatory functions, and recent insights into their immunoregulatory roles in inflammation, cancer and autoimmunity.