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Interleukin 12 (IL-12) is an interleukin that is naturally produced by macrophages and human B-lymphoblastoid cells (NC-37)in response to antigenic stimulation.
Gene and Structure
IL-12 is composed of a bundle of four alpha helices. It is a heterodimeric cytokine encoded by two separate genes, p40 and p35. The active heterodimer, and a homodimer of p40 are formed following protein synthesis.
Functions
IL-12 is involved in the differentiation of naive T cells into Th1 cells, which is important in resistance against pathogens. It is known as a T cell stimulating factor, which can stimulate the growth and function of T cells.
It stimulates the production of interferon gamma and tumor necrosis factor alpha from T and natural killer (NK) cells, and reduces IL-4 mediated suppression of interferon gamma. T cells which produce IL-12 have a coreceptor, CD30, which is associated with IL-12 activity.
IL-12 plays an important role in the actitvities of natural killer cells and T lymphocytes. IL-12 mediates enhancement of the cytotoxic activity of NK cells and CD8+ cytotoxic T lymphocytes. There also seen to be a link between IL-2 and the signal transduction of IL-12 in NK cells. IL-2 stimulates the expression of two IL-12 receptors, β1 and β2, maintaining the expression of a critical protein involved in IL-12 signaling in NK cells. Enhanced functional response is demonstrated by IFN-γ production and killing of target cells.
IL-12 also has antiangiogenic activity, which means it can block the formation of new blood vessels. It does this by increasing production of interferon gamma, which in turn increases the production of inducible protein-10 (IP-10). IP-10 then mediates this anti-angiogenic effect. Because of its ability to induce immune responses and its anti-angiogenic activity, there has been an interest in testing IL-12 as a possible anti-cancer drug. However, it has not been shown to have substantial activity in the tumors tested to this date.
Signal transduction
IL-12 binds to the IL-12 receptor, which is a heterodimeric receptor formed by β1 and β2. β2 is considered to play a key role in IL-12 function, since it is found on activated T cells and is stimulated by cytokines that promote Th1 cells development and inhibited by those that promote Th2 cells development. Upon binding, β2 becomes tyrosine phosphorylated and provides binding sites for kinases, Tyk2 and Jak2. These are important in activating critical proteins such as STAT4 which are implicated in IL-12 signaling in T cells and NK cells. This pathway is known as the JAK-STAT pathway.
IL-12 and autoimmunity
IL-12 is linked with autoimmunity. Administration of IL-12 to people suffering from autoimmune diseases was shown to worsen the autoimmune phenomena. This is believed to be due to its key role in induction of Th1 immune responses. In contrast, IL-12 gene knock-out in mice or a treatment of mice with IL-12 specific antibodies ameliorated the disease.
References
Kathy S. Wang, David A. Frank, and Jerome Ritz. Blood, Vol 95 No. 10 pp. 3183:3190 "Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4".
"Interleukin 12"