Introduction to IL-12 (Interleukin 12)

IL-12 (interleukin 12) was first described as natural killer stimulating factor in 1989. The heterodimeric cytokine IL-12 consists of a 35-kd light chain (p35 or IL-12A) and 40-kd heavy chain (p40 or IL-12B).

IL-12 product center

In the following, we will mainly discuss IL-12 (interleukin 12) & receptor, IL-12 (interleukin 12) function and IL-12 (interleukin 12) signaling Pathway.

IL-12 (Interleukin 12) & Receptor

The gene encoding p35 is located on chromosome 3 in human beings and on chromosome 6 in mice. The p35 protein contains 197 amino acids and has homology to other single-chain cytokines (eg, IL-6 and G-CSF). The IL-12 p40 gene is on the human chromosome 5 in the same area as IL-3, IL-5, and GM-CSF, and the mice gene is on chromosome 11. P40 has homology to the extracellular domain of members of hematopoietic cytokine-receptor family (eg, IL-6Rα).

Because of their localization on different chromosomes, protein expression of the 2 subunits is independently regulated, and when they are coexpressed in the same cell, they form the biologically active IL-12 p70 heterodimer. Both subunits are covalently linked by a disulfide bond between Cys74 of p35 and Cys177 of p40 to form the active IL-12 p70. IL-12p40 can be produced as a free monomer or homodimer in large excess over the IL-12p70 heterodimer in vitro and in vivo. The p40 homodimers have been suggested to antagonize IL-12p70 signaling in mice but not in human beings. That IL-12p40 acts as a macrophage chemoattractant has also been proposed. Unlike p40, p35 is not secreted in monomeric form.

IL-12 (interleukin 12) receptor, binding interleukin 12, is composed of two subunits, IL-12RB1(also known as CD212) and IL12RB2. These IL-12 functions depend on its IL-12 and IL-12 receptor complex.

IL-12 (Interleukin 12) Function

IL-12 (interleukin 12) is a heterodimeric pro-inflammatory cytokine that induces the production of interferon-γ (IFN-γ), favours the differentiation of T helper 1 (TH1) cells and forms a link between innate resistance and adaptive immunity.

Dendritic cells (DCs) and phagocytes produce IL-12 in response to pathogens during infection. Production of IL-12 is dependent on differential mechanisms of regulation of expression of the genes encoding IL-12, patterns of Toll-like receptor (TLR) expression and cross-regulation between the different DC subsets, involving cytokines such as IL-10 and type I IFN.

IL-12 (Interleukin 12) Signaling Pathway

IL-12 signaling via IL-12 (interleukin 12) receptor 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.

References

1. Akdis, M., Burgler, S., Crameri, R., Eiwegger, T., Fujita, H., Gomez, E., ... & Rhyner, C. (2011). Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. Journal of allergy and clinical immunology, 127(3), 701-721.
2. Trinchieri, G. (2003). Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature reviews. Immunology, 3(2), 133.