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
Species: mouse
Products:     Il12a

Top Publications

  1. 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...
  2. 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. ..
  3. 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. ..
  4. 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. ..
  5. 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. ..
  6. 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
  7. 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. ..
  8. 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...
  9. 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 pubmed
    Epstein-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...

More Information


  1. 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. ..
  2. 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. ..
  3. 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. ..
  4. 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
  5. 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...
  6. 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. ..
  7. 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. ..
  8. 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
  9. 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...
  10. 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 ..
  11. 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. ..
  12. 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...
  13. 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. ..
  14. 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. ..
  15. 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 pubmed
    Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits...
  16. 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
  17. 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. ..
  18. 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. ..
  19. 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
  20. 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
  21. 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. ..
  22. 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 pubmed
    IL-12 is a heterodimer of two subunits, p35 and p40, encoded by separate genes that are regulated independently...
  23. 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. ..
  24. 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 ..
  25. 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. ..
  26. 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...
  27. 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
  28. 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 ..
  29. 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...
  30. 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. ..
  31. 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
  32. 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. ..
  33. 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. ..
  34. 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. ..
  35. 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 ..
  36. 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. ..
  37. 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. ..
  38. 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. ..
  39. 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. ..
  40. 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. ..
  41. 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 pubmed
    Mice 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 ..
  42. Agarwal P, Raghavan A, Nandiwada S, Curtsinger J, Bohjanen P, Mueller D, et al. Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J Immunol. 2009;183:1695-704 pubmed publisher
  43. 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. ..
  44. 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. ..
  45. 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. ..
  46. 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
  47. 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. ..
  48. 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. ..
  49. 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. ..
  50. 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. ..
  51. 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. ..
  52. 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...
  53. Vaidyanathan H, Zhou Y, Petro T, Schwartzbach S. Intracellular localization of the p35 subunit of murine IL-12. Cytokine. 2003;21:120-8 pubmed
    Production 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...