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Gene Review

Il12a  -  interleukin 12a

Mus musculus

Synonyms: CLMF p35, Cytotoxic lymphocyte maturation factor 35 kDa subunit, IL-12 subunit p35, IL-12A, IL-12p35, ...
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Disease relevance of Il12a


High impact information on Il12a

  • Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression [6].
  • These same residues were responsible for the c-Rel requirement for Il12a induction in dendritic cells, and in both instances, no evidence of c-Rel-specific coactivator interactions was found [7].
  • Blocking GC-BP by RNA interference restores IL-12 p35 transcription and IL-12 p70 synthesis [8].
  • These results suggest that the p35 isoform of OCA-B has functions distinct from those of the nuclear p34 and that it might be a component of a signaling pathway that is required for late-stage B cell development [9].
  • Indeed, resting DC make neither the IL-12 p35 nor IL-12 p40 subunits and express only low levels of CD40 [10].

Chemical compound and disease context of Il12a


Biological context of Il12a

  • Genetic mapping of the IL-12 alpha chain gene (Il12a) on mouse chromosome 3 [14].
  • Our recent study has revealed an intimate relationship between IRF-1 and IL-12 in that IRF-1 regulates the production of IL-12 by selectively controlling transcriptional activation of IL-12 p35 gene [15].
  • Interestingly, the administration of IL-12(p40)2 also affected IL-12 gene expression, by downregulation of p35 mRNA [16].
  • Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1 [17].
  • Although LPS and CD40 cross-linking increased the T-cell allostimulatory function of BM DCs, only LPS stimulation shifted the balance of naive Th differentiation to Th1 cells, a mechanism dependent on the up-regulation of IL-12p35 and not of IL-23 [18].

Anatomical context of Il12a


Associations of Il12a with chemical compounds

  • Here we report that treatment with the homodimeric IL-12p40 subunit, an antagonist of the bioactive IL-12p35/p40 heterodimer, suppresses diabetes development in cyclophosphamide-injected NOD mice [16].
  • We now define distinct signalling mechanisms that regulate lipopolysaccharide (LPS)-mediated induction of IL-12 p40 and p35 in macrophages and which may therefore provide therapeutic targets for precise and specific fine-tuning of cytokine responses [21].
  • The effect of spermine was post-transcriptional, because steady-state levels of messenger ribonucleic acid (mRNAs) for IL-12 (p35 and p40) were not affected [22].
  • Levels of IL-12 p35 mRNA expression were comparable in cultured LNC prepared from allergen and vehicle treated mice and remained constant throughout the entire culture period [23].
  • This was confirmed by mRNA analysis, which showed that H(2)O(2) increased LPS-induced mRNA expression of both IL-12p40 and IL-12p35 subunits with an increased p40/p35 ratio [24].

Other interactions of Il12a

  • The IFN-gamma deficiency of endotoxin tolerance correlated with 8-fold decreases in the bioactive p40/p35 heterodimeric form of IL-12 [25].
  • RESULTS: While IL-12p35 appeared dispensable for the development of arthritis, IL-4 was crucial for full development of disease [26].
  • In contrast, IRF-1(-/-), but not IRF-2(-/-), macrophages exhibited impaired LPS-induced IL-12 p35 mRNA expression [27].
  • In contrast, lower mRNA transcripts for IL-12p35, IL-12p40, IL-23p19, and iNOS were detected in macrophages obtained from cestode-infected mice compared to uninfected and Leishmania-infected mice after LPS stimulation [28].
  • TNBS-treated IL-12Rbeta1(-/-) and IL-12p35(-/-) mice developed only a mild disease associated with low level IL-18 expression in IL-12p35(-/-) mice [29].

Analytical, diagnostic and therapeutic context of Il12a

  • In purified microglial cultures from neonatal mouse brains, expression of IL-12 p35 and p40 mRNA is induced by LPS and is stimulated maximally by combined IFN-gamma/LPS treatment, as detected by semiquantitative reverse-transcriptase PCR [20].
  • Using gene-targeted mice lacking only IL-12 (p35-/-) or IL-23 (p19-/-), we show that the specific absence of IL-23 is protective, whereas loss of IL-12 exacerbates collagen-induced arthritis [30].
  • In this study four murine IL-12 naked DNA expression plasmids (pIL-12), containing both the p35 and p40 subunits, were shown to induce systemic biological effects in vivo after intradermal injection [31].
  • Compared with normal mice RT-PCR products encoding both the p35 and p40 subunits of IL-12 were markedly increased in the kidney of MRL-Fas(lpr) [32].
  • One day after KA treatment, levels of F4/80 and CD86 expression on microglia were significantly lower in IL-12p35 KO mice than in wild-type mice analyzed by flow cytometry, indicating that IL-12p35 deficiency resulted in lower levels of microglial activation [11].


  1. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. Lieberman, L.A., Cardillo, F., Owyang, A.M., Rennick, D.M., Cua, D.J., Kastelein, R.A., Hunter, C.A. J. Immunol. (2004) [Pubmed]
  2. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. Cooper, A.M., Kipnis, A., Turner, J., Magram, J., Ferrante, J., Orme, I.M. J. Immunol. (2002) [Pubmed]
  3. 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. Gran, B., Zhang, G.X., Yu, S., Li, J., Chen, X.H., Ventura, E.S., Kamoun, M., Rostami, A. J. Immunol. (2002) [Pubmed]
  4. A profibrotic function of IL-12p40 in experimental pulmonary fibrosis. Huaux, F., Arras, M., Tomasi, D., Barbarin, V., Delos, M., Coutelier, J.P., Vink, A., Phan, S.H., Renauld, J.C., Lison, D. J. Immunol. (2002) [Pubmed]
  5. IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. Fairweather, D., Frisancho-Kiss, S., Yusung, S.A., Barrett, M.A., Davis, S.E., Steele, R.A., Gatewood, S.J., Rose, N.R. J. Immunol. (2005) [Pubmed]
  6. Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression. Chang, Y., Ostling, P., Akerfelt, M., Trouillet, D., Rallu, M., Gitton, Y., El Fatimy, R., Fardeau, V., Le Crom, S., Morange, M., Sistonen, L., Mezger, V. Genes Dev. (2006) [Pubmed]
  7. A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. Sanjabi, S., Williams, K.J., Saccani, S., Zhou, L., Hoffmann, A., Ghosh, G., Gerondakis, S., Natoli, G., Smale, S.T. Genes Dev. (2005) [Pubmed]
  8. Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Kim, S., Elkon, K.B., Ma, X. Immunity (2004) [Pubmed]
  9. Identification and characterization of a novel OCA-B isoform. implications for a role in B cell signaling pathways. Yu, X., Wang, L., Luo, Y., Roeder, R.G. Immunity (2001) [Pubmed]
  10. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Schulz, O., Edwards, A.D., Schito, M., Aliberti, J., Manickasingham, S., Sher, A., Reis e Sousa, C. Immunity (2000) [Pubmed]
  11. IL-12p35 deficiency alleviates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice. Chen, Z., Duan, R.S., Q, H.C., Wu, Q., Mix, E., Winblad, B., Ljunggren, H.G., Zhu, J. Neurobiol. Dis. (2004) [Pubmed]
  12. Differential expression of mRNA encoding interleukin-12 p35 and p40 subunits in situ. Bette, M., Jin, S.C., Germann, T., Schäfer, M.K., Weihe, E., Rüde, E., Fleischer, B. Eur. J. Immunol. (1994) [Pubmed]
  13. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. Casares, N., Pequignot, M.O., Tesniere, A., Ghiringhelli, F., Roux, S., Chaput, N., Schmitt, E., Hamai, A., Hervas-Stubbs, S., Obeid, M., Coutant, F., Métivier, D., Pichard, E., Aucouturier, P., Pierron, G., Garrido, C., Zitvogel, L., Kroemer, G. J. Exp. Med. (2005) [Pubmed]
  14. Genetic mapping of the IL-12 alpha chain gene (Il12a) on mouse chromosome 3. Schweitzer, P.A., Noben-Trauth, N., Pelsue, S.C., Johnson, K.R., Wolf, S.F., Shultz, L.D. Mamm. Genome (1996) [Pubmed]
  15. Role of IFN regulatory factor-1 and IL-12 in immunological resistance to pathogenesis of N-methyl-N-nitrosourea-induced T lymphoma. Liu, J., Xiang, Z., Ma, X. J. Immunol. (2004) [Pubmed]
  16. Suppression of cyclophosphamide induced diabetes development and pancreatic Th1 reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12(p40)2. Rothe, H., O'Hara, R.M., Martin, S., Kolb, H. Diabetologia (1997) [Pubmed]
  17. Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1. Liu, J., Cao, S., Herman, L.M., Ma, X. J. Exp. Med. (2003) [Pubmed]
  18. Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation. Morelli, A.E., Zahorchak, A.F., Larregina, A.T., Colvin, B.L., Logar, A.J., Takayama, T., Falo, L.D., Thomson, A.W. Blood (2001) [Pubmed]
  19. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. Becher, B., Durell, B.G., Noelle, R.J. J. Clin. Invest. (2002) [Pubmed]
  20. IL-12 production by central nervous system microglia is inhibited by astrocytes. Aloisi, F., Penna, G., Cerase, J., Menéndez Iglesias, B., Adorini, L. J. Immunol. (1997) [Pubmed]
  21. Differential regulation of interleukin-12 p40 and p35 induction via Erk mitogen-activated protein kinase-dependent and -independent mechanisms and the implications for bioactive IL-12 and IL-23 responses. Goodridge, H.S., Harnett, W., Liew, F.Y., Harnett, M.M. Immunology (2003) [Pubmed]
  22. Spermine differentially regulates the production of interleukin-12 p40 and interleukin-10 and suppresses the release of the T helper 1 cytokine interferon-gamma. Haskó, G., Kuhel, D.G., Marton, A., Nemeth, Z.H., Deitch, E.A., Szabó, C. Shock (2000) [Pubmed]
  23. Analysis of interleukin 12 protein production and mRNA expression in mice exposed topically to chemical allergens. Warbrick, E.V., Dearman, R.J., Basketter, D.A., Kimber, I. Toxicology (1999) [Pubmed]
  24. Hydrogen peroxide increases interleukin-12 p40/p70 molecular ratio and induces Th2-predominant responses in mice. Obata, F., Hoshino, A., Toyama, A. Scand. J. Immunol. (2006) [Pubmed]
  25. Endotoxin fails to induce IFN-gamma in endotoxin-tolerant mice: deficiencies in both IL-12 heterodimer production and IL-12 responsiveness. Balkhy, H.H., Heinzel, F.P. J. Immunol. (1999) [Pubmed]
  26. Interleukin-4 can be a key positive regulator of inflammatory arthritis. Ohmura, K., Nguyen, L.T., Locksley, R.M., Mathis, D., Benoist, C. Arthritis Rheum. (2005) [Pubmed]
  27. IL-12 is dysregulated in macrophages from IRF-1 and IRF-2 knockout mice. Salkowski, C.A., Kopydlowski, K., Blanco, J., Cody, M.J., McNally, R., Vogel, S.N. J. Immunol. (1999) [Pubmed]
  28. Acute cysticercosis favours rapid and more severe lesions caused by Leishmania major and Leishmania mexicana infection, a role for alternatively activated macrophages. Rodríguez-Sosa, M., Rivera-Montoya, I., Espinoza, A., Romero-Grijalva, M., López-Flores, R., González, J., Terrazas, L.I. Cell. Immunol. (2006) [Pubmed]
  29. Contrasting roles of IL-12p40 and IL-12p35 in the development of hapten-induced colitis. Camoglio, L., Juffermans, N.P., Peppelenbosch, M., te Velde, A.A., ten Kate, F.J., van Deventer, S.J., Kopf, M. Eur. J. Immunol. (2002) [Pubmed]
  30. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. Murphy, C.A., Langrish, C.L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R.A., Sedgwick, J.D., Cua, D.J. J. Exp. Med. (2003) [Pubmed]
  31. Intradermal delivery of IL-12 naked DNA induces systemic NK cell activation and Th1 response in vivo that is independent of endogenous IL-12 production. Watanabe, M., Fenton, R.G., Wigginton, J.M., McCormick, K.L., Volker, K.M., Fogler, W.E., Roessler, P.G., Wiltrout, R.H. J. Immunol. (1999) [Pubmed]
  32. Up-regulation of tubular epithelial interleukin-12 in autoimmune MRL-Fas(lpr) mice with renal injury. Fan, X., Oertli, B., Wüthrich, R.P. Kidney Int. (1997) [Pubmed]
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