Interleukin 12 subunit beta
Subunit beta of interleukin 12 (also known as IL-12B, natural killer cell stimulatory factor 2, or cytotoxic lymphocyte maturation factor 2, p40) is a protein that in humans is encoded by the IL12B gene. IL-12B is a subunit of interleukin 12.
Function
This gene encodes a subunit of interleukin 12, a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. Interleukin 12 is a disulfide-linked heterodimer composed of the 40 kD cytokine receptor like subunit encoded by this gene, and a 35 kD subunit encoded by IL12A. This cytokine is expressed by activated macrophages that serve as an essential inducer of Th1 cells development. This cytokine has been found to be important for sustaining a sufficient number of memory/effector Th1 cells to mediate long-term protection to an intracellular pathogen. Overexpression of this gene was observed in the central nervous system of patients with multiple sclerosis (MS), suggesting a role of this cytokine in the pathogenesis of the disease. The promoter gene polymorphism of this gene has been reported to be associated with the severity of atopic and non-atopic asthma in children.[1]
Structure
Editing results in an amino acid change from an alanine to a valine may cause a conformational change in the IL12 receptor.[2]
Function
Editing causes a reduction in the extent of IL-12 signaling as the β subunit is involved in signal transduction. This leads to insufficient IFN-γ production, possibly due to an interruption of the binding of IL-12 to its receptor. Binding may be restricted due to a conformational change caused by the change of amino acid. The change in the signaling cascade and reduction of IFN-γ effects downregulation of IgE. Atrophy patients have enhanced IgE sensitivity to everyday environmental factors such as asthma. This is the only editing event linked to atrophy.[2]
RNA editing
Interleukin 12 receptor, beta 2 subunit(IL12Rβ2) is a product of the IL12-R β2 gene. As previously mentioned, the gene product is one of two subunits which combine to form the IL-12 receptor.The other subunit being IL12-R β1 subunit.[3] The β2 subunit is only expressed in Th1 lymphocytes.The pre-mRNA of the IL12-R β2 gene is subject to RNA editing.
Editing type
Cytidine to Uridine (C to U) RNA editing.
Editing sites
The editing site is located at nucleotide 2451 which is found in exon 13 which forms part of the extracellular domain of the protein.[2] However another report was unable to detect this C to U conversion[4]
Role as IL-23 subunit
Interleukin-12 p40 also serves as a subunit of Interleukin 23.[5]
Clinical significance
There is an increase in the frequency of editing in Atopic patients (20.6%) from that non atopic patients (3.8%) transcripts.This is the first reported case that indicates that atopy could be associated with RNA editing.Atopy is characterized by enhanced immunoglobulin E (IgE) responses to common environmental antigens and leads to clinical disorders such as asthma, eczema and rhinitis.[2]
References
- ↑ "Entrez Gene: IL12B interleukin 12B (natural killer cell stimulatory factor 2, cytotoxic lymphocyte maturation factor 2, p40)".
- ↑ 2.0 2.1 2.2 2.3 Kondo N, Matsui E, Kaneko H, Aoki M, Kato Z, Fukao T, Kasahara K, Morimoto N (March 2004). "RNA editing of interleukin-12 receptor beta2, 2451 C-to-U (Ala 604 Val) conversion, associated with atopy". Clin. Exp. Allergy 34 (3): 363–8. doi:10.1111/j.1365-2222.2004.01901.x. PMID 15005728.
- ↑ Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, Gately MK, Gubler U (November 1996). "A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits". Proc. Natl. Acad. Sci. U.S.A. 93 (24): 14002–7. doi:10.1073/pnas.93.24.14002. PMC 19484. PMID 8943050.
- ↑ Kim EJ, Lee WM, Ha JS, Ryoo NH, Jeon DS, Kim JR (December 2006). "mRNA Expression and RNA Editing (2451 C-to-U) of IL-12 Receptor β2 in Adult Atopic Patients". J. Korean Med. Sci. 21 (6): 1070–4. doi:10.3346/jkms.2006.21.6.1070. PMC 2721931. PMID 17179689.
- ↑ Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (November 2000). "Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12". Immunity 13 (5): 715–25. doi:10.1016/S1074-7613(00)00070-4. PMID 11114383.
Further reading
- Airoldi I, Guglielmino R, Carra G, Corcione A, Gerosa F, Taborelli G, Trinchieri G, Pistoia V (2002). "The interleukin-12 and interleukin-12 receptor system in normal and transformed human B lymphocytes". Haematologica 87 (4): 434–42. PMID 11940489.
- Abdi K (2002). "IL-12: the role of p40 versus p75". Scand. J. Immunol. 56 (1): 1–11. doi:10.1046/j.1365-3083.2002.01101.x. PMID 12100467.
- Sieburth D, Jabs EW, Warrington JA, Li X, Lasota J, LaForgia S, Kelleher K, Huebner K, Wasmuth JJ, Wolf SF (1992). "Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5". Genomics 14 (1): 59–62. doi:10.1016/S0888-7543(05)80283-6. PMID 1358798.
- Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz C, Hewick RM (1991). "Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells". J. Immunol. 146 (9): 3074–81. PMID 1673147.
- Gubler U, Chua AO, Schoenhaut DS, Dwyer CM, McComas W, Motyka R, Nabavi N, Wolitzky AG, Quinn PM, Familletti PC (1991). "Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor". Proc. Natl. Acad. Sci. U.S.A. 88 (10): 4143–7. doi:10.1073/pnas.88.10.4143. PMC 51614. PMID 1674604.
- Gearing DP, Cosman D (1991). "Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor". Cell 66 (1): 9–10. doi:10.1016/0092-8674(91)90131-H. PMID 2070420.
- Stern AS, Podlaski FJ, Hulmes JD, Pan YC, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R (1990). "Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells". Proc. Natl. Acad. Sci. U.S.A. 87 (17): 6808–12. doi:10.1073/pnas.87.17.6808. PMC 54627. PMID 2204066.
- Aragane Y, Riemann H, Bhardwaj RS, Schwarz A, Sawada Y, Yamada H, Luger TA, Kubin M, Trinchieri G, Schwarz T (1995). "IL-12 is expressed and released by human keratinocytes and epidermoid carcinoma cell lines". J. Immunol. 153 (12): 5366–72. PMID 7527439.
- Ling P, Gately MK, Gubler U, Stern AS, Lin P, Hollfelder K, Su C, Pan YC, Hakimi J (1995). "Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity". J. Immunol. 154 (1): 116–27. PMID 7527811.
- Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM (1995). "Regulation of interleukin 12 p40 expression through an NF-kappa B half-site". Mol. Cell. Biol. 15 (10): 5258–67. PMC 230773. PMID 7565674.
- Sharma V, Knobloch TJ, Benjamin D (1995). "Differential expression of cytokine genes in HIV-1 tat transfected T and B cell lines". Biochem. Biophys. Res. Commun. 208 (2): 704–13. doi:10.1006/bbrc.1995.1395. PMID 7695626.
- Warrington JA, Bengtsson U (1995). "High-resolution physical mapping of human 5q31-q33 using three methods: radiation hybrid mapping, interphase fluorescence in situ hybridization, and pulsed-field gel electrophoresis". Genomics 24 (2): 395–8. doi:10.1006/geno.1994.1636. PMID 7698768.
- D'Andrea A, Ma X, Aste-Amezaga M, Paganin C, Trinchieri G (1995). "Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production". J. Exp. Med. 181 (2): 537–46. doi:10.1084/jem.181.2.537. PMC 2191875. PMID 7836910.
- Gillessen S, Carvajal D, Ling P, Podlaski FJ, Stremlo DL, Familletti PC, Gubler U, Presky DH, Stern AS, Gately MK (1995). "Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist". Eur. J. Immunol. 25 (1): 200–6. doi:10.1002/eji.1830250133. PMID 7843232.
- Radrizzani M, Accornero P, Amidei A, Aiello A, Delia D, Kurrle R, Colombo MP (1995). "IL-12 inhibits apoptosis induced in a human Th1 clone by gp120/CD4 cross-linking and CD3/TCR activation or by IL-2 deprivation". Cell. Immunol. 161 (1): 14–21. doi:10.1006/cimm.1995.1003. PMID 7867080.
- Ma X, Chow JM, Gri G, Carra G, Gerosa F, Wolf SF, Dzialo R, Trinchieri G (1996). "The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells". J. Exp. Med. 183 (1): 147–57. doi:10.1084/jem.183.1.147. PMC 2192398. PMID 8551218.
- Fantuzzi L, Gessani S, Borghi P, Varano B, Conti L, Puddu P, Belardelli F (1996). "Induction of interleukin-12 (IL-12) by recombinant glycoprotein gp120 of human immunodeficiency virus type 1 in human monocytes/macrophages: requirement of gamma interferon for IL-12 secretion". J. Virol. 70 (6): 4121–4. PMC 190299. PMID 8648753.
- Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G (1996). "Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation". J. Exp. Med. 184 (2): 747–52. doi:10.1084/jem.184.2.747. PMC 2192696. PMID 8760829.
- Kato K, Shimozato O, Hoshi K, Wakimoto H, Hamada H, Yagita H, Okumura K (1996). "Local production of the p40 subunit of interleukin 12 suppresses T-helper 1-mediated immune responses and prevents allogeneic myoblast rejection". Proc. Natl. Acad. Sci. U.S.A. 93 (17): 9085–9. doi:10.1073/pnas.93.17.9085. PMC 38599. PMID 8799158.
- Taoufik Y, Lantz O, Wallon C, Charles A, Dussaix E, Delfraissy JF (1997). "Human immunodeficiency virus gp120 inhibits interleukin-12 secretion by human monocytes: an indirect interleukin-10-mediated effect". Blood 89 (8): 2842–8. PMID 9108403.
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