| Human Interleukin 12 | |
|---|---|
 Crystal structure of human IL-12 | |
| Identifiers | |
| Symbol | IL12, p70 |
| PDB | 1F45 |
| IL12A | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | IL12A | ||||||
| Alt. symbols | CLMF1, NKSF1, p35 | ||||||
| NCBI gene | 3592 | ||||||
| HGNC | 5969 | ||||||
| OMIM | 161560 | ||||||
| RefSeq | NM_000882 | ||||||
| UniProt | P29459 | ||||||
| Other data | |||||||
| Locus | Chr. 3p12-q13.2 | ||||||
| |||||||
| interleukin 12B | |||||||
|---|---|---|---|---|---|---|---|
 Crystal structure of IL-12B | |||||||
| Identifiers | |||||||
| Symbol | IL12B | ||||||
| Alt. symbols | CLMF2, NKSF2, p40 | ||||||
| NCBI gene | 3593 | ||||||
| HGNC | 5970 | ||||||
| OMIM | 161561 | ||||||
| PDB | 1F42 | ||||||
| RefSeq | NM_002187 | ||||||
| UniProt | P29460 | ||||||
| Other data | |||||||
| Locus | Chr. 5q31.1-33.1 | ||||||
| |||||||
Interleukin 12 (IL-12) is aninterleukin that is naturally produced bydendritic cells,[1]macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the onlyheterodimeric cytokines, which includes IL-12,IL-23,IL-27 andIL-35.[2] Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.
IL12 is aheterodimericcytokine encoded by two separate genes,IL-12A (p35) andIL-12B (p40). The activeheterodimer (referred to as 'p70'), and ahomodimer of p40 are formed following protein synthesis.IL12A is composed of a bundle of fouralpha helices.IL12B has threebeta sheet domains.
IL-12 is involved in the differentiation of naiveT cells intoTh1 cells.[3] It is known as a T cell-stimulating factor, which can stimulate the growth and function of T cells. It stimulates the production ofinterferon-gamma (IFN-γ) andtumor necrosis factor-alpha (TNF-α) from T cells andnatural killer (NK) cells, and reducesIL-4 mediated suppression of IFN-γ.[4] T cells that produce IL-12 have acoreceptor,CD30, which is associated with IL-12 activity.
IL-12 plays an important role in the activities ofnatural killer cells and T lymphocytes. IL-12 mediates enhancement of the cytotoxic activity ofNK cells andCD8+cytotoxic T lymphocytes. There also seems to be a link betweenIL-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 inNK cells. Enhanced functional response is demonstrated byIFN-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 ofinterferon gamma, which in turn increases the production of achemokine called inducible protein-10 (IP-10 orCXCL10). 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 thetumors tested to this date. Recent preclinical studies have shown that targeted delivery of IL-12 via nanoparticles can enhance IL-12’s antitumor activity in metastatic ovarian cancer. In mouse models, liposomal nanoparticles coated with poly-L-arginine and poly-L-glutamate were engineered to slowly release IL-12 directly into tumor sites, resulting in strong T-cell infiltration, allowing cytotoxic T cells to recognize and attack tumor cells and thereby significantly extending survival.[5] There is a link that may be useful in treatment between IL-12 and the diseases psoriasis & inflammatory bowel disease.[citation needed] There has also been research indicating that interleukin 12 is linked with interleukin 23 and antibodies against these factors have a possible role in creating an anti-inflammatory effect in inflammatory bowel disease.[6]
IL-12 binds to the IL-12 receptor, which is a heterodimeric receptor formed byIL-12Rβ1 andIL-12Rβ2.[7] IL-12Rβ2 is considered to play a key role in IL-12 function, since it is found on activatedT cells and is stimulated by cytokines that promoteTh1 cells development and inhibited by those that promoteTh2 cells development. Upon binding, IL-12R-β2 becomes tyrosine phosphorylated and provides binding sites for kinases,Tyk2 andJak2. These are important in activating criticaltranscription factor proteins such asSTAT4 that are implicated in IL-12 signaling inT cells and NK cells. This pathway is known as theJAK-STAT pathway.[8]
An extensive review and visualization of IL-12 signaling can be found at the peer-reviewed pathway databaseReactome: Interleukin-12 family
IL-12 is linked withautoimmunity. Administration of IL-12 to people suffering fromautoimmune 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-12gene knock-out in mice or a treatment of mice with IL-12 specific antibodies ameliorated the disease.
Results published in theJournal 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 from developing. Further investigation is underway, to determine whether the results found in mice are as profound in humans.[9][10]
Interleukin 12 (IL-12) is produced by activated antigen-presenting cells (dendritic cells,macrophages).[11] It promotes the development ofTh1 responses and is a powerful inducer ofIFNγ production by T andNK cells.[12]
A child withBacillus Calmette–Guérin andSalmonella enteritidis infection was found to have a largehomozygous deletion within the IL-12 p40 subunit gene, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. As a result, IFNγ production by the child's lymphocytes was markedly impaired.[13]This suggested that IL-12 is essential for protective immunity to intracellular bacteria such asmycobacteria andSalmonella.
Support is lent to this idea by the observation that areceptor for IL-12 is important for IFNγ production by lymphocytes. T and NK cells from seven unrelated patients who had severe idiopathic mycobacterial andSalmonella infections failed to produce IFNγ when stimulated with IL-12.[13] The patients were otherwise healthy. They were found to have mutations in the IL-12 receptor β1 chain, resulting inpremature stop codons in the extracellular domain, resulting in unresponsiveness to this cytokine, again demonstrating IL-12's crucial role in host defense.
Defective Th1 and Th17 immune responses leading tochronic mucocutaneous candidiasis result from a mutation further downstream in the IL-12signalling pathway. The trait was mapped to mutations in theSTAT1 gene, which were associated with lower production of interferon-γ, IL-17, and IL-22 in response to IL-12 or IL-23 receptor associatedJak2 andTyk2 activity.[14]
