Interleukin 12 a key immunoregulatory cytokine in infection applications

Abstract

Interleukin 12 (termed IL-12p70 and commonly designated IL-12) is an important immunoregulatory cytokine that is produced mainly by antigen-presenting cells. The expression of IL-12 during infection regulates innate responses and determines the type of adaptive immune responses. IL-12 induces interferon-gamma (IFN-gamma) production and triggers CD4(+) T cells to differentiate into type 1 T helper (Th1) cells. Studies have suggested that IL-12 could play a vital role in treating many diseases, such as viral and bacterial infections and cancers. The unique heterodimeric structure, which IL-12 shares with its family members including IL-23, IL-27, and IL-35, has recently brought more attention to understanding the mechanisms that regulate the functions of IL-12. This article describes the structure and biological activities of IL-12 in both the innate and adaptive arms of the immune system, and discusses the applications of IL-12 in treating and preventing infections.

Keywords: cell signaling; cell-mediated immunity; infection; interferon-γ; interleukin 12.

Figure 1.

Crystal structure of IL-12. IL-12 is composed of a bundle of four alpha helices. It is a heterodimeric cytokine encoded by two separate genes, IL-12p35 and IL-12p40. Obtained from the Protein Data Bank (PDB: 1F45).

Figure 2.

The IL-12 cytokine family; structural and biological characteristics. Reprinted from Ref. [13].

Figure 3.

IL-12 signaling pathway. IL-12 activates the Jak/STAT pathway. Following binding of IL-12p40 and IL-12p35 to IL-12R β1 and IL-12R β2, respectively, Jak-2 and Tyk-2 get transphosphorylated. Phosphorylated IL-12R β2 binds to STAT4 which will then dimerize with another STAT4 molecule. STAT4 homodimers translocate to the nucleus and promote IFN-γ gene transcription. T-bet is another transcription factor that plays a role in Th1 development and IFN-γ production. The IL-12 and IFN-γ induce the activity and proliferation of MΦs, NK cells, and T cells, which also secrete IL-12. Modified from Ref. [34].

Figure 4.

Summary of the biology of IL-12 [14]. The main physiological producers of IL-12 are phagocytes (monocytes/MΦ and neutrophils) and DCs in response to pathogens (bacteria, fungi, intracellular parasites and viruses) through TLRs and other receptors, to membrane-bound and soluble signals from activated T cells and NK cells, and to components of the inflammatory extracellular matrix (for example, low-molecular-weight hyaluronan) through CD44 and TLRs. The physiologically most important target cells of IL-12 are: haematopoietic progenitors, for which, in synergy with other colony-stimulating factors, IL-12 induces increased proliferation and colony formation; NK cells, NK T cells and T cells, for which IL-12 induces proliferation, enhancement of cytotoxicity and of the expression of cytotoxic mediators, and the production of cytokines, particularly IFN-γ, as well as favoring differentiation to cells that produce type-1 cytokines (Th1, TC1 and NK1 cells); and B cells, for which IL-12, directly or through the effects of type-1 cytokines such as IFN-γ, enhances the activation and production of Th1-associated classes of immunoglobulin (for example, IgG2a in the mouse). CTL, cytotoxic T lymphocyte; GM-CSF, granulocyte macrophage colony-stimulating factor; RANKL, receptor activator of nuclear factor-κB ligand; SCF, stem-cell factor; TC1, T cytotoxic 1; TH1/Th1, T helper 1; TNF, tumor-necrosis factor. Reprinted from Ref. [14].

Figure 5.

Local IL-12 therapy stimulates Th cells to secrete Th1 cytokines. Exogenous IL-12 application creates an environment rich in IL-12 around the infection site. In such a local environment, newly activated Th cells, responding to the presence of bacteria, exit the blood and are influenced to become Th1 cells and secrete more Th1 cytokines and activate macrophages and NK cells. Activated macrophages will produce more IL-12 and via positive feedback, cell-mediated immunity can be promoted to battle bacteria thereby leading to the prevention of infection. Reprinted from Ref. [69].