Interleukin-12
From Proteopedia
BackgroundInterleukin-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 isIL-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 highlightsIL-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] FunctionInterleukin-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 stimulated 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 eat 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 your immune system reacts to an allergen. All those actions that IL-12 performs helps it with its antitumor effects. In animal studies IL-12 has been useful in tumor therapy. [2] Its effectiveness is also increased when used with other therapeutic models. IL-12 is proinflammatory meaning it promotes inflammation which contributes in developing th1 cells from th0 cells. [4] It also participates in a positive feed back loop. IL-12 causes interferon gamma production from t cells. That facilitated th1 differentiation. IL-12 also induced production of interferon gamma by natural killer cells. [4] Interferon gamma can be a part of the positive feed back 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] DiseasesIf 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 over expressed 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 more. 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 FamilyIL-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 all 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 is doesn’t secrete much when not in the presence of p40. [5] References
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