||It has been suggested that IL-12 and IL-12 Receptor β1 Mutations be merged into this article. (Discuss) Proposed since July 2011.|
|Human Interleukin 12|
Crystal structure of human IL-12
|PDB||1F45 (RCSB PDB PDBe PDBj)|
|Alt. symbols||CLMF1, NKSF1, p35|
|Locus||Chr. 3 p12-q13.2|
Crystal structure of IL-12B
|Alt. symbols||CLMF2, NKSF2, p40|
|PDB||1F42 (RCSB PDB PDBe PDBj)|
|Locus||Chr. 5 q31.1-33.1|
Gene and structure
IL-12 is composed of a bundle of four alpha helices. It is a heterodimeric cytokine encoded by two separate genes, IL-12A (p35) and IL-12B (p40). The active heterodimer, and a homodimer of p40 are formed following protein synthesis.
IL-12 is involved in the differentiation of naive T cells into Th1 cells. 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 (IFN-γ) and tumor necrosis factor-alpha (TNF-α) from T and natural killer (NK) cells, and reduces IL-4 mediated suppression of IFN-γ. T cells that produce IL-12 have a coreceptor, CD30, which is associated with IL-12 activity.
IL-12 plays an important role in the activities 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 seems 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, IL-12R-β1 and IL-12R-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 anti-angiogenic 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 a chemokine called inducible protein-10 (IP-10 or CXCL10). 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. There is a link that may be useful in treatment between IL-12 and the diseases psoriasis and inflammatory bowel disease.
IL-12 binds to the IL-12 receptor, which is a heterodimeric receptor formed by IL-12R-β1 and IL-12R-β2. IL-12R-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, IL-12R-β2 becomes tyrosine phosphorylated and provides binding sites for kinases, Tyk2 and Jak2. These are important in activating critical transcription factor proteins such as STAT4 that 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.
Results published in the Journal of Allergy and Clinical Immunology from a study where mice that were bred to be allergic to peanuts, Interleukin-12 has been shown to not be present, suggesting that the molecule normally stops allergies to food developing. Further investigation is underway, to determine whether the results found in mice are as profound in humans.
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- Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM (April 1993). "Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages". Science 260 (5107): 547–9. PMID 8097338.
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- Temblay JN, Bertelli E, Arques JL, Regoli M, Nicoletti C (September 2007). "Production of IL-12 by Peyer patch-dendritic cells is critical for the resistance to food allergy". J. Allergy Clin. Immunol. 120 (3): 659–65. doi:10.1016/j.jaci.2007.04.044. PMID 17599398.
- "Food allergy molecule discovered". BBC News. 1 July 2007.