Background
Interleukin-12 also known as IL-12, is produced by many different cells such as macrophages, B cells, and neutrophils. These cells produce IL-12 to generate immunity to pathogens. It can also stimulate the proliferation of natural killer cells, which are cells that can specifically target and kill cells that have been affected by pathogens. IL-12 is also a heterodimeric glycoprotein. This means that IL-12 has two subunits that are linked by a di-sulfide bond. That di-sulfide bond is not necessary for the formation of IL-12. It is also not necessary for the secretion of IL-12, but the di-sulfide bonds help to stabilize the subunits. There have been studies done to see its effects on immunotherapy.
What it is
IL-12 is a cytokine. A cytokine is a small protein that signals the immune responses between lymphocytes and phagocytes to influence the production of antibodies.
Structural highlights
IL-12 is a heterodimer, meaning it has two polypeptide chains that differ in their composition and number of amino acids. These polypeptide chains have carbohydrates attached, meaning that IL-12 is also a glycoprotein. It has two disulfide linked subunits p35 and . [1] The p35 subunit is similar in structure to other class 1 cytokines. The p40 subunit is similar to hematopoietic cytokines. Hematopoietic cytokines make hematopoietic cells turn into different blood cells. P35 is unstable without p40 and can not be secreted, but p40 can function without p35. [1] P35 has a long chain four-helix bundle that binds to a soluble alpha chain receptor subunit, which is p40.[1] There is an that projects from the p35 into a pocket in p40. That pocket could be a spot for an inhibitor to bind, so IL-12 cannot form. When p35 and p40 combine they form IL-12, which is also known as p70. When looking at the disulfide bond between p35 and p40 they found it is not necessary to form and secrete IL-12, but it makes sure there is stabilization between these subunits. [1]
Function
Interleukin-12 is produced by macrophages, neutrophils, and some B cells. IL-12 helps make cytotoxic cells and natural killer cells. T cells turn into cytotoxic t cells when IL-12 is released. [1]
Innate immunity is when the body has defense mechanisms that start working within hours of a pathogen being introduced into the body. Innate is the first line of defense against all pathogens, so there is no specificity pathogens; they attack anything. Adaptive immunity is acquired or specific. It is supposed to attack pathogens that are invading. If the immune system attacks the host organism, an autoimmune disorder develops. Adaptive immunity is done by B or T lymphoctyes. T helper cells secrete different cytokines like IL-12, which lets IL-12 activate innate natural killer cells and adaptive cytotoxic t cells.[2] IL-12 helps mature cytotoxic T cells so they can attack specific pathogens. [2] It also helps stimulate the production of natural killer cells so they can start innate immunity. IL-12 is also produced by dendritic cells and monocytes.
To increase the production of IL-12 it can be done through priming or amplification. [2] In priming, IL-12 would bind to the receptors on a ligand allowing it to move through the immune system faster. Amplification happens through a cytokine network where different cytokines get secreted through different cells.
IL-12 has many actions. One action is stimulating the growth and cytotoxicity of natural killer cells. They also convert th0 cells into th1 cells by activating specific transcription factors. [2] IL-12 also stimulates the production of which is another type of cytokine used in innate and adaptive immunity. [2] Interferon gamma is secreted by T cells and natural killer cells; also it promotes macrophage activation, meaning it helps more macrophages to be activated so it can phagocytose bacteria, viruses, and fungi. [3] IL-12 also helped to introduce IgG and suppress IgE from B cells. IgG is the most common antibody released from plasma B cells and has two antigen binding sites. IgE is an antibody that is produced when the immune system reacts to an allergen. All those actions that IL-12 performs help it with its anti-tumor effects. In animal studies, IL-12 has been useful in tumor therapy. [2] Its effectiveness increases when used with other therapeutic models.
IL-12 is proinflammatory, meaning it promotes inflammation which contributes to developing th1 cells from th0 cells. [4] It also participates in a positive feedback loop. IL-12 causes interferon gamma production from T cells that facilitates th1 differentiation. IL-12 also induced the production of interferon gamma by natural killer cells. [4] Interferon gamma can be a part of the positive feedback loop because transcription factors are activated. In a study done on mice, if specific transcription factors are not expressed, there can be a defect in one or both subunits of IL-12. [5]
Diseases
If there is a deficiency in IL-12 then cell mediated immunity becomes impaired. [5] That makes organisms more susceptible to diseases. If interleukin-12 is overexpressed, it could lead to persistent inflammation which is harmful for some autoimmune disorders like multiple sclerosis. [5] It is harmful because it makes the immune system attack cells of the host more often. IL-12 can be protective or detrimental depending on the infection it is aiding in attacking. It can work with other cytokines to inhibit the infectivity of HIV in macrophages. [5] With all the various functions IL-12 partakes in it could be helpful in immunotherapy for some infections.
IL-12 Family
IL-12 is apart of the interleukin-12 family. The family consist of IL-12, , IL-27, and IL-35. [4]They are all heterodimeric cytokines. They are structurally similar, but have very different biological activities. IL-23 also has two disulfide linked subunits. One subunit both IL-23 and IL-12 share is p40. [5] IL-23's other subunit acts very similary to p35 in IL-12. That subunit is p19 and it does not secrete much when not in the presence of p40. [5]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Yoon C, Johnston SC, Tang J, Stahl M, Tobin JF, Somers WS. Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. EMBO J. 2000 Jul 17;19(14):3530-41. PMID:10899108 doi:http://dx.doi.org/10.1093/emboj/19.14.3530
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Lasek W, Zagozdzon R, Jakobisiak M. Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother. 2014 May;63(5):419-35. doi: 10.1007/s00262-014-1523-1., Epub 2014 Feb 11. PMID:24514955 doi:http://dx.doi.org/10.1007/s00262-014-1523-1
- ↑ Tau G, Rothman P. Biologic functions of the IFN-gamma receptors. Allergy. 1999 Dec;54(12):1233-51. doi: 10.1034/j.1398-9995.1999.00099.x. PMID:10688427 doi:http://dx.doi.org/10.1034/j.1398-9995.1999.00099.x
- ↑ 4.0 4.1 4.2 Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012 Jul 19;13(8):722-8. doi: 10.1038/ni.2366. PMID:22814351 doi:http://dx.doi.org/10.1038/ni.2366
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Gee K, Guzzo C, Che Mat NF, Ma W, Kumar A. The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm Allergy Drug Targets. 2009 Mar;8(1):40-52. doi:, 10.2174/187152809787582507. PMID:19275692 doi:http://dx.doi.org/10.2174/187152809787582507
