Interleukin 12

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Structures	Swiss-model
Domains	InterPro

IL12A
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. 3 p12-q13.2
Structures
Search for
Structures	Swiss-model
Domains	InterPro

Human Interleukin 12
Human Interleukin 12
	Crystal structure of human IL-12 (red helices)
Identifiers
Symbol	IL12, p70
PDB	1F45

Last updated February 27, 2024

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. 5 q31.1-33.1

Search for
Structures	Swiss-model
Domains	InterPro

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic 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 only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35.^[2] Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

Gene and structure

IL12 is a heterodimeric cytokine encoded by two separate genes, IL-12A (p35) and IL-12B (p40). The active heterodimer (referred to as 'p70'), and a homodimer of p40 are formed following protein synthesis. IL12A is composed of a bundle of four alpha helices. IL12B has three beta sheet domains.

Functions

IL-12 is involved in the differentiation of naive T cells into Th1 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 of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) from T cells and natural killer (NK) cells, and reduces IL-4 mediated suppression of IFN-γ.^[4] 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 & 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. ^[5]

Signal transduction

IL-12 binds to the IL-12 receptor, which is a heterodimeric receptor formed by IL-12Rβ1 and IL-12Rβ2.^[6] IL-12Rβ2 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.^[7]

An extensive review and visualization of IL-12 signaling can be found at the peer-reviewed pathway database Reactome: Interleukin-12 family

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 from developing. Further investigation is underway, to determine whether the results found in mice are as profound in humans.^[8]^[9]

IL-12 and IL-12 receptor β1 mutations

Interleukin 12 (IL-12) is produced by activated antigen-presenting cells (dendritic cells, macrophages).^[10] It promotes the development of Th1 responses and is a powerful inducer of IFNγ production by T and NK cells.^[11]

A child with Bacillus Calmette–Guérin and Salmonella enteritidis infection was found to have a large homozygous 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.^[12] This suggested that IL-12 is essential for protective immunity to intracellular bacteria such as mycobacteria and Salmonella .

Support is lent to this idea by the observation that a receptor for IL-12 is important for IFNγ production by lymphocytes. T and NK cells from seven unrelated patients who had severe idiopathic mycobacterial and Salmonella infections failed to produce IFNγ when stimulated with IL-12.^[12] The patients were otherwise healthy. They were found to have mutations in the IL-12 receptor β1 chain, resulting in premature 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 to chronic mucocutaneous candidiasis result from a mutation further downstream in the IL-12 signalling pathway. The trait was mapped to mutations in the STAT1 gene, which were associated with lower production of interferon-γ, IL-17, and IL-22 in response to IL-12 or IL-23 receptor associated Jak2 and Tyk2 activity.^[13]

Related Research Articles

The T helper cells (T_h cells), also known as CD4⁺ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4⁺ cells are mature T_h cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4⁺ cells determines susceptibility to a broad class of autoimmune diseases.

Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (T_h0 cells) to T_h2 cells. Upon activation by IL-4, T_h2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, T_h2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.

Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. The protein is also known as IL-23p19. It is one of the two subunits of the cytokine Interleukin-23.

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells. Originally, IL-18 production was recognized in Kupffer cells, liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

Interleukin 27 (IL-27) is a member of the IL-12 cytokine family. It is a heterodimeric cytokine that is encoded by two distinct genes, Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28. IL-27 is expressed by antigen presenting cells and interacts with a specific cell-surface receptor complex known as IL-27 receptor (IL-27R). This receptor consists of two proteins, IL-27Rɑ and gp130. IL-27 induces differentiation of the diverse populations of T cells in the immune system and also upregulates IL-10.

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

Interleukin-22 (IL-22) is protein that in humans is encoded by the IL22 gene.

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

Understanding of the antitumor immunity role of CD4⁺ T cells has grown substantially since the late 1990s. CD4⁺ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.

Subunit beta of interleukin 12 is a protein subunit that in humans is encoded by the IL12B gene. IL-12B is a common subunit of interleukin 12 and interleukin 23.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 consists of a heterodimer between IL-12Rβ1 and IL-23R.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disease. It is a primary immunodeficiency featured by molecular defects in IL12/IFNγ dependent signalling pathway, leading to increased susceptibility to local or disseminated infections by environmental mycobacteria, Mycobacterium bovis Bacille Calmette-Guerin strain, nontyphoidal and typhoidal Salmonella serotypes.

References

↑ Kaliński P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML (July 1997). "IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells". Journal of Immunology. 159 (1): 28–35. doi:10.4049/jimmunol.159.1.28. PMID 9200435. S2CID 10617490.
↑ Vignali DA, Kuchroo VK (July 2012). "IL-12 family cytokines: immunological playmakers". Nature Immunology. 13 (8): 722–8. doi:10.1038/ni.2366. PMC 4158817 . PMID 22814351.
↑ 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. Bibcode:1993Sci...260..547H. doi:10.1126/science.8097338. PMID 8097338.
↑ Zheng H, Ban Y, Wei F, Ma X (2016), Ma X (ed.), "Regulation of Interleukin-12 Production in Antigen-Presenting Cells", Regulation of Cytokine Gene Expression in Immunity and Diseases, Advances in Experimental Medicine and Biology, Springer Netherlands, vol. 941, pp. 117–138, doi:10.1007/978-94-024-0921-5_6, ISBN 978-94-024-0919-2, PMID 27734411
↑ Kashani A, Schwartz D (May 2019). "The Expanding Role of Anti–IL-12 and/or Anti–IL-23 Antibodies in the Treatment of Inflammatory Bowel Disease". Gastroenterology & Hepatology. 15 (5): 255–265. PMC 6589846 . PMID 31360139.
↑ Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, et al. (November 1996). "A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits". Proceedings of the National Academy of Sciences of the United States of America. 93 (24): 14002–7. Bibcode:1996PNAS...9314002P. doi: 10.1073/pnas.93.24.14002 . PMC 19484 . PMID 8943050.
↑ Wang KS, Frank DA, Ritz J (May 2000). "Interleukin-2 enhances the response of natural killer cells to interleukin-12 through up-regulation of the interleukin-12 receptor and STAT4". Blood. 95 (10): 3183–90. doi:10.1182/blood.V95.10.3183. PMID 10807786. Archived from the original on 2013-04-15.
↑ 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". The Journal of Allergy and Clinical Immunology. 120 (3): 659–65. doi: 10.1016/j.jaci.2007.04.044 . PMID 17599398.
↑ "Food allergy molecule discovered". BBC News. 1 July 2007.
↑ Dorman SE, Holland SM (December 2000). "Interferon-gamma and interleukin-12 pathway defects and human disease". Cytokine & Growth Factor Reviews. 11 (4): 321–33. doi:10.1016/s1359-6101(00)00010-1. PMID 10959079.
↑ Newport MJ, Holland SM, Levin M, Casanova JL (2007). "Inherited disorders of the interleukin-12/23-interferon gamma axis". In Ochs HD, Smith CI, Puck J (eds.). Primary immunodeficiency diseases : a molecular and genetic approach. New York: Oxford University Press. pp. 390–401. ISBN 978-0-19-514774-2.
1 2 Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, et al. (May 1998). "Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency". Science. 280 (5368): 1432–5. Bibcode:1998Sci...280.1432A. doi:10.1126/science.280.5368.1432. PMID 9603732.
↑ van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, et al. (July 2011). "STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis". The New England Journal of Medicine. 365 (1): 54–61. doi: 10.1056/NEJMoa1100102 . PMID 21714643.

Interleukin 12

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