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Gene Review

Il12b  -  interleukin 12b

Mus musculus

Synonyms: CLMF p40, Cytotoxic lymphocyte maturation factor 40 kDa subunit, IL-12 p40, IL-12 subunit p40, IL-12B, ...
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Disease relevance of Il12b

  • These studies show that a molecule other than IL-12 p70, which uses the p40 subunit, fulfills the functions previously attributed to IL-12 with regard to the development and pathogenesis of this autoimmune disease [1].
  • Control of IL-12 p40 expression is therefore important for understanding resistance and susceptibility to a variety of pathogens, including Leishmania major and perhaps human immunodeficiency virus [2].
  • In vivo, supplementation with rIL-12p40 restored the impaired pulmonary fibrotic response and macrophage accumulation in silica-treated IL-12p40(-/-) mice, and also promoted fibrosis and macrophage influx in wild-type mice [3].
  • To determine whether this is the case in tuberculosis, both p35 and p40 knockout mice were infected with Mycobacterium tuberculosis [4].
  • Together, our data suggest that IL-12p40 plays an important role in silica-induced pulmonary inflammation and fibrosis, possibly by exacerbating macrophage recruitment [3].

High impact information on Il12b


Chemical compound and disease context of Il12b

  • In addition, chloroquine treatment suppressed IL-12 p40 production in response to Legionella treatment in dendritic cells and macrophages from BALB/c and A/J mice [10].
  • 7. Transcription from the murine p40 promoter was strongly induced by lipopolysaccharide and heat-killed Listeria monocytogenes (HKLM), but promoter activity was not enhanced by gamma interferon [11].
  • This response was induced not only by endotoxin but also by bacillus Calmette-Guerin (BCG) and CD40 ligand and was associated with (and likely caused by) the enhanced and prolonged expression of p40 mRNA [12].
  • We found that NK cell depletion following anti-NK1.1 monoclonal antibody (mAb) injections led to an increase of hepatic collagen content in the late stages of granuloma formation and to the diminution of interleukin 12 (IL-12) p40 and IL-7 mRNA expression in the livers [13].
  • We previously found that an extracellular polysaccharide, AC-1, produced by Acetobacter polysaccharogenes composed of (1,4)-beta-D-glucan with branches of glucosyl residues showed a strong activity to induce production of interleukin (IL)-12 p40 and tumor necrosis factor-alpha by macrophage cell lines in vitro via Toll-like receptor-4 signaling [14].

Biological context of Il12b


Anatomical context of Il12b

  • Immature ICSBP(-/-) DCs developed from BM progenitor cells showed assorted defects, did not mature in response to activation signals, and failed to express CD8alpha and interleukin 12 (IL-12) p40, a feature consistent with ICSBP(-/-) DCs in vivo [19].
  • Here, EAN was established in IL-12 p40 deficient mutant (IL-12-/-) C57BL/6 mice by immunization with P0 peptide 180-199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant [20].
  • As a consequence, the NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibits lipopolysaccharide (LPS)-induced IL-12 p40 mRNA expression, protein production, and promoter activity in murine macrophages, dendritic cells, and the murine macrophage cell line RAW 264 [17].
  • Because nitric oxide produced from the induction of nitric-oxide synthase (iNOS) also plays a vital role in the pathophysiology of MS, the present study was undertaken to explore the role of p40 in the induction of NO production and the expression of iNOS in microglia [21].
  • Transgenic mice were developed with expression of either both the IL-12 subunits (p35 and p40) or only the IL-12 p40 subunit genes targeted to astrocytes in the mouse CNS [22].

Associations of Il12b with chemical compounds


Physical interactions of Il12b

  • In the present study, we demonstrated that IRF-1 directly binds to the IL-12 p40 gene promoter and identified its binding site [18].
  • Aberrant production of IL-12 by macrophages from several autoimmune-prone mouse strains is characterized by intrinsic and unique patterns of NF-kappa B expression and binding to the IL-12 p40 promoter [27].
  • Evaluation of the possible mechanism(s) underlying the abnormal regulation of IL-12 in these strains revealed novel patterns of Rel family protein binding to the unique p40 NF-kappaB site in the IL-12 p40 promoter, whereas binding patterns to Ets and CCAAT enhancer binding protein/beta sites were normal [27].

Regulatory relationships of Il12b


Other interactions of Il12b

  • This selective defect in IL-12 p40 production was observed regardless of whether the macrophages had been primed with IFN-gamma [15].
  • Analysis of cytokine synthesis in vitro and in vivo revealed a major deficiency in the expression of both interferon (IFN)-gamma and interleukin (IL)-12 p40 in the T. gondii exposed ICSBP-/- animals [15].
  • Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells [21].
  • The -63 to -61 position is the critical site within this region for the binding of IRF-1 to the IL-12 p40 gene promoter [18].
  • IL-12 p40-deficient mice (which lack IL-12 and IL-23) and OSM receptor-deficient mice were susceptible to mBSA/IL-1-induced arthritis [31].

Analytical, diagnostic and therapeutic context of Il12b


  1. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. Becher, B., Durell, B.G., Noelle, R.J. J. Clin. Invest. (2002) [Pubmed]
  2. Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Murphy, T.L., Cleveland, M.G., Kulesza, P., Magram, J., Murphy, K.M. Mol. Cell. Biol. (1995) [Pubmed]
  3. 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]
  4. 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]
  5. The human interferon alpha/beta receptor: characterization and molecular cloning. Novick, D., Cohen, B., Rubinstein, M. Cell (1994) [Pubmed]
  6. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Cua, D.J., Sherlock, J., Chen, Y., Murphy, C.A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S.A., Gorman, D., Kastelein, R.A., Sedgwick, J.D. Nature (2003) [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. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Stark, M.A., Huo, Y., Burcin, T.L., Morris, M.A., Olson, T.S., Ley, K. Immunity (2005) [Pubmed]
  9. 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]
  10. Role of Toll-Like Receptor 9 in Legionella pneumophila-Induced Interleukin-12 p40 Production in Bone Marrow-Derived Dendritic Cells and Macrophages from Permissive and Nonpermissive Mice. Newton, C.A., Perkins, I., Widen, R.H., Friedman, H., Klein, T.W. Infect. Immun. (2007) [Pubmed]
  11. Multiple control elements mediate activation of the murine and human interleukin 12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins. Plevy, S.E., Gemberling, J.H., Hsu, S., Dorner, A.J., Smale, S.T. Mol. Cell. Biol. (1997) [Pubmed]
  12. Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice. Alleva, D.G., Pavlovich, R.P., Grant, C., Kaser, S.B., Beller, D.I. Diabetes (2000) [Pubmed]
  13. Schistosoma mansoni-infected mice show augmented hepatic fibrosis and selective inhibition of liver cytokine production after treatment with anti-NK1.1 antibodies. Asseman, C., Pancré, V., Quatennens, B., Auriault, C. Immunol. Lett. (1996) [Pubmed]
  14. Soluble branched (1,4)-beta-D-glucans from Acetobacter species enhance antitumor activities against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response. Kamiryo, Y., Yajima, T., Saito, K., Nishimura, H., Fushimi, T., Ohshima, Y., Tsukamoto, Y., Naito, S., Yoshikai, Y. Int. J. Cancer (2005) [Pubmed]
  15. Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. Scharton-Kersten, T., Contursi, C., Masumi, A., Sher, A., Ozato, K. J. Exp. Med. (1997) [Pubmed]
  16. Activation of the murine interleukin-12 p40 promoter by functional interactions between NFAT and ICSBP. Zhu, C., Rao, K., Xiong, H., Gagnidze, K., Li, F., Horvath, C., Plevy, S. J. Biol. Chem. (2003) [Pubmed]
  17. Inhibition of interleukin-12 p40 transcription and NF-kappaB activation by nitric oxide in murine macrophages and dendritic cells. Xiong, H., Zhu, C., Li, F., Hegazi, R., He, K., Babyatsky, M., Bauer, A.J., Plevy, S.E. J. Biol. Chem. (2004) [Pubmed]
  18. Identification of IFN regulatory factor-1 binding site in IL-12 p40 gene promoter. Maruyama, S., Sumita, K., Shen, H., Kanoh, M., Xu, X., Sato, M., Matsumoto, M., Shinomiya, H., Asano, Y. J. Immunol. (2003) [Pubmed]
  19. ICSBP/IRF-8 retrovirus transduction rescues dendritic cell development in vitro. Tsujimura, H., Tamura, T., Gongora, C., Aliberti, J., Reis e Sousa, C., Sher, A., Ozato, K. Blood (2003) [Pubmed]
  20. The critical role of IL-12p40 in initiating, enhancing, and perpetuating pathogenic events in murine experimental autoimmune neuritis. Bao, L., Lindgren, J.U., van der Meide, P., Zhu, S., Ljunggren, H.G., Zhu, J. Brain Pathol. (2002) [Pubmed]
  21. Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells. Pahan, K., Sheikh, F.G., Liu, X., Hilger, S., McKinney, M., Petro, T.M. J. Biol. Chem. (2001) [Pubmed]
  22. Astrocyte-targeted expression of IL-12 induces active cellular immune responses in the central nervous system and modulates experimental allergic encephalomyelitis. Pagenstecher, A., Lassmann, S., Carson, M.J., Kincaid, C.L., Stalder, A.K., Campbell, I.L. J. Immunol. (2000) [Pubmed]
  23. Hydrogen peroxide inhibits IL-12 p40 induction in macrophages by inhibiting c-rel translocation to the nucleus through activation of calmodulin protein. Khan, N., Rahim, S.S., Boddupalli, C.S., Ghousunnissa, S., Padma, S., Pathak, N., Thiagarajan, D., Hasnain, S.E., Mukhopadhyay, S. Blood (2006) [Pubmed]
  24. 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]
  25. 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]
  26. Mechanisms of strain-dependent development of mast cells from mouse splenocytes. Hu, Z.Q., Zhao, W.H., Shimamura, T. Immunol. Cell Biol. (2006) [Pubmed]
  27. Aberrant production of IL-12 by macrophages from several autoimmune-prone mouse strains is characterized by intrinsic and unique patterns of NF-kappa B expression and binding to the IL-12 p40 promoter. Liu, J., Beller, D. J. Immunol. (2002) [Pubmed]
  28. Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages. Jana, M., Dasgupta, S., Saha, R.N., Liu, X., Pahan, K. J. Neurochem. (2003) [Pubmed]
  29. IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice. Shiraki, M., Aihara, H., Kinouchi, Y., Takahashi, S., Oki, M., Noguchi, M., Takahashi, K., Miyazaki, J., Shimosegawa, T. Lab. Invest. (2004) [Pubmed]
  30. Signaling through CD40 ligand decreases CD80 expression on murine Langerhans cells and enhances IL-12 p40 production. Sugaya, M., Nakamura, K., Asahina, A., Fujita, H., Tada, Y., Torii, H., Tamaki, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  31. Acute CD4+ T lymphocyte-dependent interleukin-1-driven arthritis selectively requires interleukin-2 and interleukin-4, joint macrophages, granulocyte-macrophage colony-stimulating factor, interleukin-6, and leukemia inhibitory factor. Lawlor, K.E., Wong, P.K., Campbell, I.K., van Rooijen, N., Wicks, I.P. Arthritis Rheum. (2005) [Pubmed]
  32. Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages. Peng, X., Mosser, D.M., Adler, M.W., Rogers, T.J., Meissler, J.J., Eisenstein, T.K. J. Leukoc. Biol. (2000) [Pubmed]
  33. 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]
  34. 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]
  35. Pulmonary immune responses during primary mycobacterium bovis- Calmette-Guerin bacillus infection in C57Bl/6 mice. Fulton, S.A., Martin, T.D., Redline, R.W., Henry Boom, W. Am. J. Respir. Cell Mol. Biol. (2000) [Pubmed]
  36. Dendritic cells and the regulation of a granulomatous immune response in the lung. Iyonaga, K., McCarthy, K.M., Schneeberger, E.E. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
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