Genomes and Genes
Gene Symbol: Il12a
Description: interleukin 12a
Alias: IL-12p35, Il-12a, Ll12a, p35, interleukin-12 subunit alpha, CLMF p35, IL-12 p35 subunit, IL-12 subunit p35, cytotoxic lymphocyte maturation factor 35 kDa subunit, interleukin 12a p35 subunit, interleukin-12 p35 subunit
- Becher B, Durell B, Noelle R. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest. 2002;110:493-7 pubmed..IL-12 is a heterodimer composed of a p35 subunit and a common p40 subunit shared by other cytokines...
- Pearce E, Shen H. Generation of CD8 T cell memory is regulated by IL-12. J Immunol. 2007;179:2074-81 pubmed..These results have implications for understanding memory T cell development and enhancing vaccine efficacy, and offer new insight into the role of IL-12 in coordinating the innate and adaptive immune response. ..
- Langowski J, Zhang X, Wu L, Mattson J, Chen T, Smith K, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461-5 pubmed..We show that IL-23 is an important molecular link between tumour-promoting pro-inflammatory processes and the failure of the adaptive immune surveillance to infiltrate tumours. ..
- Shaw M, Freeman G, Scott M, Fox B, Bzik D, Belkaid Y, et al. Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation. J Immunol. 2006;176:7263-71 pubmed..Thus, Tyk2 can be viewed as a dual-function Jak, mediating both pro and anti-inflammatory cytokine responses. ..
- Freudenberg M, Merlin T, Kalis C, Chvatchko Y, Stübig H, Galanos C. Cutting edge: a murine, IL-12-independent pathway of IFN-gamma induction by gram-negative bacteria based on STAT4 activation by Type I IFN and IL-18 signaling. J Immunol. 2002;169:1665-8 pubmed..This pathway participates in the induction of IFN-gamma by Gram-negative bacteria and is therefore expected to play a role whenever IFN-alpha or IFN-beta and IL-18 are produced concomitantly during bacterial, viral, or other infections. ..
- Demangel C, Bertolino P, Britton W. Autocrine IL-10 impairs dendritic cell (DC)-derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL-12 production. Eur J Immunol. 2002;32:994-1002 pubmed
- Iborra S, Soto M, Stark Aroeira L, Castellano E, Alarcon B, Alonso C, et al. H-ras and N-ras are dispensable for T-cell development and activation but critical for protective Th1 immunity. Blood. 2011;117:5102-11 pubmed publisher..Furthermore, we demonstrate for the first time that H-ras and N-ras act as critical controllers of Th1 responses, mostly by transmitting TCR signals for Th1 priming of CD4? T cells. ..
- Lieberman L, Cardillo F, Owyang A, Rennick D, Cua D, Kastelein R, et al. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J Immunol. 2004;173:1887-93 pubmed..gondii, mice lacking the p40 subunit (common to IL-12 and IL-23) and mice that lack IL-12 p35 (specific for IL-12) were infected and their responses were compared...
- Niedbala W, Wei X, Cai B, Hueber A, Leung B, McInnes I, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol. 2007;37:3021-9 pubmedEpstein-Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12 have been reported to form a heterodimeric hematopoietin in human and mouse...
- Pien G, Satoskar A, Takeda K, Akira S, Biron C. Cutting edge: selective IL-18 requirements for induction of compartmental IFN-gamma responses during viral infection. J Immunol. 2000;165:4787-91 pubmed..Taken together, our results delineate contrasting compartmental requirements for IL-18 and suggest that preservation of local, hepatic IFN-gamma production is critical for host defense during murine cytomegalovirus challenge. ..
- Collison L, Chaturvedi V, Henderson A, Giacomin P, Guy C, Bankoti J, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11:1093-101 pubmed publisher..Thus, iT(R)35 cells constitute a key mediator of infectious tolerance and contribute to T(reg) cell-mediated tumor progression. Furthermore, iT(R)35 cells generated ex vivo might have therapeutic utility. ..
- Holscher C, Atkinson R, Arendse B, Brown N, Myburgh E, Alber G, et al. A protective and agonistic function of IL-12p40 in mycobacterial infection. J Immunol. 2001;167:6957-66 pubmed..Together, these results show evidence for a protective and agonistic role of endogenous and exogenous IL-12p40 in mycobacterial infection, which is independent of IL-12p70. ..
- Cousens L, Peterson R, Hsu S, Dorner A, Altman J, Ahmed R, et al. Two roads diverged: interferon alpha/beta- and interleukin 12-mediated pathways in promoting T cell interferon gamma responses during viral infection. J Exp Med. 1999;189:1315-28 pubmed
- Conti H, Shen F, Nayyar N, Stocum E, Sun J, Lindemann M, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009;206:299-311 pubmed publisher..Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors...
- Lin Y, Ritchea S, Logar A, Slight S, Messmer M, Rangel Moreno J, et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity. 2009;31:799-810 pubmed publisher..Together, these findings illustrate a biological function for IL-17A in regulating IL-12-Th1 cell immunity and host responses to an intracellular pathogen. ..
- Zelante T, De Luca A, Bonifazi P, Montagnoli C, Bozza S, Moretti S, et al. IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol. 2007;37:2695-706 pubmed..As IL-23-driven inflammation promotes infection and impairs antifungal resistance, modulation of the inflammatory response represents a potential strategy to stimulate protective immune responses to fungi. ..
- Spörri R, Reis E Sousa C. Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat Immunol. 2005;6:163-70 pubmed
- Town T, Bai F, Wang T, Kaplan A, Qian F, Montgomery R, et al. Toll-like receptor 7 mitigates lethal West Nile encephalitis via interleukin 23-dependent immune cell infiltration and homing. Immunity. 2009;30:242-53 pubmed publisher..and mice deficient in IL-12 p40 and IL-23 p40 (Il12b(-/-)) or IL-23 p19 (Il23a(-/-)), but not IL-12 p35 (Il12a(-/-)), responded similarly to Tlr7(-/-) mice, with increased susceptibility to lethal WNV encephalitis...
- Gillessen S, Carvajal D, Ling P, Podlaski F, Stremlo D, Familletti P, et al. Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist. Eur J Immunol. 1995;25:200-6 pubmed..has regulatory effects on T and natural killer (NK) cells and is composed of two disulfide-bonded subunits, p40 and p35. It was recently reported that supernatants from cultures of mouse IL-12 (moIL-12) p40-transfected COS cells could ..
- Chen Q, Ghilardi N, Wang H, Baker T, Xie M, Gurney A, et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature. 2000;407:916-20 pubmed..Our results demonstrate the existence of a new cytokine receptor involved in regulating the adaptive immune response and critical to the generation of a Th1 response. ..
- Gran B, Zhang G, Yu S, Li J, Chen X, Ventura E, et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol. 2002;169:7104-10 pubmed..IL-12 is a heterodimeric cytokine, composed of a p40 and a p35 subunit, which is thought to play an important role in the development of Th1 cells and can exacerbate EAE...
- Becker C, Dornhoff H, Neufert C, Fantini M, Wirtz S, Huebner S, et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol. 2006;177:2760-4 pubmed..Taken together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis. ..
- Way S, Havenar Daughton C, Kolumam G, Orgun N, Murali Krishna K. IL-12 and type-I IFN synergize for IFN-gamma production by CD4 T cells, whereas neither are required for IFN-gamma production by CD8 T cells after Listeria monocytogenes infection. J Immunol. 2007;178:4498-505 pubmed..These results demonstrate an important dichotomy between the signals required for priming IFN-gamma production by CD4 and CD8 T cells in response to bacterial infection. ..
- Cua D, Sherlock J, Chen Y, Murphy C, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421:744-8 pubmedInterleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits...
- Nguyen K, Salazar Mather T, Dalod M, Van Deusen J, Wei X, Liew F, et al. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol. 2002;169:4279-87 pubmed
- Teng M, Andrews D, McLaughlin N, von Scheidt B, Ngiow S, Möller A, et al. IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. Proc Natl Acad Sci U S A. 2010;107:8328-33 pubmed publisher..Overall, these data indicate the general role that IL-23 plays in suppressing natural or cytokine-induced innate immunity, promoting tumor development and metastases independently of IL-17A. ..
- Luger D, Silver P, Tang J, Cua D, Chen Z, Iwakura Y, et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med. 2008;205:799-810 pubmed publisher..These data also raise the possibility that the nonredundant requirement for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and help provide a balance in the current Th1 versus Th17 paradigm. ..
- Davidson N, Hudak S, Lesley R, Menon S, Leach M, Rennick D. IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol. 1998;161:3143-9 pubmed
- Khader S, Pearl J, Sakamoto K, Gilmartin L, Bell G, Jelley Gibbs D, et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-gamma responses if IL-12p70 is available. J Immunol. 2005;175:788-95 pubmed
- Flynn J, Goldstein M, Triebold K, Sypek J, Wolf S, Bloom B. IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection. J Immunol. 1995;155:2515-24 pubmed..tuberculosis-infected gko mice, transgenic mice in which the IFN-gamma gene has been disrupted, indicating that IL-12 does not induce protection against tuberculosis in mice in the absence of IFN-gamma. ..
- Babik J, Adams E, Tone Y, Fairchild P, Tone M, Waldmann H. Expression of murine IL-12 is regulated by translational control of the p35 subunit. J Immunol. 1999;162:4069-78 pubmedIL-12 is a heterodimer of two subunits, p35 and p40, encoded by separate genes that are regulated independently...
- Gorbachev A, Fairchild R. CD40 engagement enhances antigen-presenting langerhans cell priming of IFN-gamma-producing CD4+ and CD8+ T cells independently of IL-12. J Immunol. 2004;173:2443-52 pubmed..These results indicate that hpLC stimulated by CD40 ligation use a mechanism distinct from increased IL-12 production to promote Ag-specific T cell development to IFN-gamma-producing cells. ..
- Schijns V, Haagmans B, Wierda C, Kruithof B, Heijnen I, Alber G, et al. Mice lacking IL-12 develop polarized Th1 cells during viral infection. J Immunol. 1998;160:3958-64 pubmed..In this study, we demonstrate that mice with a targeted disruption of the IL-12p40 and/or p35 gene effectively control liver damage induced by mouse hepatitis virus (MHV) infection, similar to wild-type ..
- Pakpour N, Zaph C, Scott P. The central memory CD4+ T cell population generated during Leishmania major infection requires IL-12 to produce IFN-gamma. J Immunol. 2008;180:8299-305 pubmed..Thus, continued IL-12 production may be required to ensure the development of Th1 cells from this central memory T cell pool, a finding that has direct relevance to the design of vaccines dependent upon central memory CD4(+) T cells. ..
- Shafiani S, Dinh C, Ertelt J, Moguche A, Siddiqui I, Smigiel K, et al. Pathogen-specific Treg cells expand early during mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12. Immunity. 2013;38:1261-70 pubmed publisher..These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity...
- Pan P, Gu P, Li Q, Xu D, Weber K, Chen S. Regulation of dendritic cell function by NK cells: mechanisms underlying the synergism in the combination therapy of IL-12 and 4-1BB activation. J Immunol. 2004;172:4779-89 pubmed
- Schulz S, Kohler G, Schütze N, Knauer J, Straubinger R, Chackerian A, et al. Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17. J Immunol. 2008;181:7891-901 pubmed..To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35(-/-) mice (lacking IL-12), p35/19(-/-) mice (lacking IL-12 and IL-23), p35/40(-/-) mice (lacking IL-12, IL-23, and ..
- Schoenhaut D, Chua A, Wolitzky A, Quinn P, Dwyer C, McComas W, et al. Cloning and expression of murine IL-12. J Immunol. 1992;148:3433-40 pubmed..the murine subunits with their human counterparts revealed that the p40 subunits are more highly conserved than the p35 subunits (70% vs 60% identity, respectively). The sizes of the p35 and p40 subunit mRNA were estimated to be 1...
- Diefenbach A, Schindler H, Rollinghoff M, Yokoyama W, Bogdan C. Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science. 1999;284:951-5 pubmed..Activation of Tyk2 in NK cells by IFN-alpha/beta also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity. ..
- Takemoto N, Intlekofer A, Northrup J, Wherry E, Reiner S. Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. J Immunol. 2006;177:7515-9 pubmed
- Valenzuela J, Hammerbeck C, Mescher M. Cutting edge: Bcl-3 up-regulation by signal 3 cytokine (IL-12) prolongs survival of antigen-activated CD8 T cells. J Immunol. 2005;174:600-4 pubmed..The time courses of expression suggest that Bcl-2 and Bcl-x(L) promote survival early in the response, whereas Bcl-3 acts later in the response. ..
- Keppler S, Rosenits K, Koegl T, Vucikuja S, Aichele P. Signal 3 cytokines as modulators of primary immune responses during infections: the interplay of type I IFN and IL-12 in CD8 T cell responses. PLoS ONE. 2012;7:e40865 pubmed publisher..Furthermore our results demonstrate that the pathogen-induced overall inflammatory milieu and not the antigen load and/or the quality of antigen presentation critically determine the signal 3 dependence of CD8 T cells. ..
- Huaux F, Arras M, Tomasi D, Barbarin V, Delos M, Coutelier J, et al. A profibrotic function of IL-12p40 in experimental pulmonary fibrosis. J Immunol. 2002;169:2653-61 pubmed..Together, our data suggest that IL-12p40 plays an important role in silica-induced pulmonary inflammation and fibrosis, possibly by exacerbating macrophage recruitment. ..
- Collison L, Workman C, Kuo T, Boyd K, Wang Y, Vignali K, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566-9 pubmed..we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27beta) and interleukin-12 alpha (Il12a, which encodes IL-12alpha/p35) are highly expressed by mouse Foxp3+ (forkhead box P3) T(reg) cells but not by ..
- Vasconcellos R, Carter N, Rosser E, Mauri C. IL-12p35 subunit contributes to autoimmunity by limiting IL-27-driven regulatory responses. J Immunol. 2011;187:3402-12 pubmed publisher..The restoration of disease phenotype after anti-IL-27 administration indicates that the IL-12p35 subunit acts as negative regulator of the developing IL-27 response in this model of arthritis. ..
- Murphy T, Cleveland M, Kulesza P, Magram J, Murphy K. Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol. 1995;15:5258-67 pubmed..Finally, we find that IFN-gamma treatment of cells enhances this binding interaction, thus potentially providing a mechanism for IFN-gamma augmentation of IL-12 production by macrophages. ..
- Magram J, Connaughton S, Warrier R, Carvajal D, Wu C, Ferrante J, et al. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity. 1996;4:471-81 pubmed..However, other phenomena associated with Th1 responses and cell-mediated immunity, i.e., IL-2 secretion and CTL generation, were not compromised in the absence of IL-12. ..
- Tarrant T, Silver P, Chan C, Wiggert B, Caspi R. Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis. J Immunol. 1998;161:122-7 pubmed..Lastly, the diminished ability of primed wt lymphocytes to induce EAU in 12KO mice indicates a role for endogenous IL-12 in the efferent phase of disease expression that is distinct from its role during Ag priming. ..
- Obar J, Jellison E, Sheridan B, Blair D, Pham Q, Zickovich J, et al. Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J Immunol. 2011;187:4967-78 pubmed publisher..Thus, our data shed light on how varying the context of T cell priming alters downstream effector and memory CD8(+) T cell differentiation. ..
- Mattner F, Magram J, Ferrante J, Launois P, Di Padova K, Behin R, et al. Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response. Eur J Immunol. 1996;26:1553-9 pubmedMice with homologous disruption of the gene coding for either the p35 subunit or the p40 subunit of interleukin-12 (IL-12) and derived from a strain genetically resistant to infection with Leishmania major have been used to study further ..
- Xiao Z, Casey K, Jameson S, Curtsinger J, Mescher M. Programming for CD8 T cell memory development requires IL-12 or type I IFN. J Immunol. 2009;182:2786-94 pubmed publisher..These data demonstrate that IL-12 and type I IFN play an essential early role in determining whether Ag encounter by naive CD8 T cells results in formation of a protective memory population. ..
- Liese J, Schleicher U, Bogdan C. TLR9 signaling is essential for the innate NK cell response in murine cutaneous leishmaniasis. Eur J Immunol. 2007;37:3424-34 pubmed..We conclude that TLR9 signaling is essential for NK cell activation, but dispensable for a protective T cell response to L. major in vivo. ..
- McIntyre K, Shuster D, Gillooly K, Warrier R, Connaughton S, Hall L, et al. Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur J Immunol. 1996;26:2933-8 pubmed..Taken together, these results demonstrate an important role for IL-12 in the pathogenesis of CIA, although it is not absolutely required for disease development. ..
- Wilson D, Matthews S, Yap G. IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii Infection. J Immunol. 2008;180:5935-45 pubmed..gondii...
- Mashayekhi M, Sandau M, Dunay I, Frickel E, Khan A, Goldszmid R, et al. CD8?(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites. Immunity. 2011;35:249-59 pubmed publisher..These results reveal that the function of CD8?(+) DCs extends beyond a role in cross-presentation and includes a critical role for activation of innate immunity through IL-12 production during T. gondii infection. ..
- Rutitzky L, Lopes da Rosa J, Stadecker M. Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol. 2005;175:3920-6 pubmed..Our findings indicate that an IL-17-producing T cell population, likely driven by IL-23, significantly contributes to severe immunopathology in schistosomiasis. ..
- Skokos D, Nussenzweig M. CD8- DCs induce IL-12-independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. J Exp Med. 2007;204:1525-31 pubmed..Thus, activation of the two DC subsets by TLR4 leads to Th1 responses by two distinct MyD88-dependent pathways. ..
- Satoskar A, Rodig S, Telford S, Satoskar A, Ghosh S, Von Lichtenberg F, et al. IL-12 gene-deficient C57BL/6 mice are susceptible to Leishmania donovani but have diminished hepatic immunopathology. Eur J Immunol. 2000;30:834-9 pubmed..These findings indicate that although endogenous IL-12 is critical for the development of protective immunity to L. donovani, it is also responsible for inducing the significant immunopathology associated with visceral leishmaniasis. ..
- Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116:1310-6 pubmed..This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases. ..
- Cooper A, Kipnis A, Turner J, Magram J, Ferrante J, Orme I. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J Immunol. 2002;168:1322-7 pubmed..of the IL-12p40 subunit is more detrimental to the generation of protective responses than is the absence of the p35 subunit...
- Vaidyanathan H, Zhou Y, Petro T, Schwartzbach S. Intracellular localization of the p35 subunit of murine IL-12. Cytokine. 2003;21:120-8 pubmedProduction of interleukin-12 (IL-12), a heterodimer of p35 and p40 subunits, is limited by p35 expression. A long and a short murine p35 mRNA potentially encoding proteins differing in pre-sequence size are produced...