Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity - PubMed (original) (raw)
. 1995 Jan 1;154(1):116-27.
Affiliations
- PMID: 7527811
Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity
P Ling et al. J Immunol. 1995.
Abstract
IL-12, a heterodimeric cytokine, consists of two disulfide-linked subunits, p40 and p35. We investigated the role of p40 in ligand binding and signal transduction by expressing this subunit alone in COS cells. Culture media of the transfected COS cells exhibited specific dose-dependent binding to KIT225/K6 cells, a human T cell line that expresses IL-12R. Analysis of the culture media by SDS-PAGE and Western blotting demonstrated the presence of 40-kDa monomers and 80-kDa disulfide-linked homodimers. The two p40 species were purified and identified by N-terminal sequencing and proteolytic peptide mapping. Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125I-labeled IL-12 binding to IL-12R, but the 80-kDa species, having a 50% inhibitory concentration (IC50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. Although neither the monomer nor the dimer stimulated human PHA-blast proliferation, the 80-kDa dimer inhibited IL-12-induced proliferation in a dose-dependent manner with an IC50 of 65 ng/ml. The results suggest that the IL-12 p40 subunit contains the essential epitopes for receptor binding. However, a proper conformation required for high affinity binding is achieved only when p40 is associated with a p35 subunit or another p40 subunit. When p40 is associated with a p35 subunit, the heterodimer acts as an agonist mediating biologic activity. However, when p40 associates with another p40, the homodimer behaves as an antagonist in vitro.
Similar articles
- Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist.
Gillessen S, Carvajal D, Ling P, Podlaski FJ, Stremlo DL, Familletti PC, Gubler U, Presky DH, Stern AS, Gately MK. Gillessen S, et al. Eur J Immunol. 1995 Jan;25(1):200-6. doi: 10.1002/eji.1830250133. Eur J Immunol. 1995. PMID: 7843232 - Analysis of the multiple interactions between IL-12 and the high affinity IL-12 receptor complex.
Presky DH, Minetti LJ, Gillessen S, Wilkinson VL, Wu CY, Gubler U, Chizzonite R, Gately MK. Presky DH, et al. J Immunol. 1998 Mar 1;160(5):2174-9. J Immunol. 1998. PMID: 9498755 - IL-12: monoclonal antibodies specific for the 40-kDa subunit block receptor binding and biologic activity on activated human lymphoblasts.
Chizzonite R, Truitt T, Podlaski FJ, Wolitzky AG, Quinn PM, Nunes P, Stern AS, Gately MK. Chizzonite R, et al. J Immunol. 1991 Sep 1;147(5):1548-56. J Immunol. 1991. PMID: 1715362 - The interleukin-12 and interleukin-12 receptor system in normal and transformed human B lymphocytes.
Airoldi I, Guglielmino R, Carra G, Corcione A, Gerosa F, Taborelli G, Trinchieri G, Pistoia V. Airoldi I, et al. Haematologica. 2002 Apr;87(4):434-42. Haematologica. 2002. PMID: 11940489 Review. - Novel IL-12 family members shed light on the orchestration of Th1 responses.
Brombacher F, Kastelein RA, Alber G. Brombacher F, et al. Trends Immunol. 2003 Apr;24(4):207-12. doi: 10.1016/s1471-4906(03)00067-x. Trends Immunol. 2003. PMID: 12697453 Free PMC article. Review.
Cited by
- Post-translational modifications and immune responses in liver cancer.
Wang YW, Zuo JC, Chen C, Li XH. Wang YW, et al. Front Immunol. 2023 Jul 11;14:1230465. doi: 10.3389/fimmu.2023.1230465. eCollection 2023. Front Immunol. 2023. PMID: 37609076 Free PMC article. Review. - Human IL-35 Inhibits the Bioactivity of IL-12 and Its Interaction with IL-12Rβ2.
Mahfooz NS, Merling MR, Claeys TA, Dowling JW, Forero A, Robinson RT. Mahfooz NS, et al. Immunohorizons. 2023 Jun 1;7(6):431-441. doi: 10.4049/immunohorizons.2300039. Immunohorizons. 2023. PMID: 37289499 Free PMC article. - IFNγ is a central node of cancer immune equilibrium.
Walsh MJ, Stump CT, Kureshi R, Lenehan P, Ali LR, Dougan M, Knipe DM, Dougan SK. Walsh MJ, et al. Cell Rep. 2023 Mar 28;42(3):112219. doi: 10.1016/j.celrep.2023.112219. Epub 2023 Mar 6. Cell Rep. 2023. PMID: 36881506 Free PMC article. - Impact of Chronic Rhinosinusitis with Nasal Polyposis on IL-12 and IL-8.
do Amaral JB, David AG, Mello L, Bachi ALL, Voegels RL, Thamboo A, Pezato R. do Amaral JB, et al. Iran J Otorhinolaryngol. 2023 Jan;35(126):21-27. doi: 10.22038/IJORL.2022.53663.2829. Iran J Otorhinolaryngol. 2023. PMID: 36721412 Free PMC article. - Human IL12p80 Promotes Murine Oligodendrocyte Differentiation to Repair Nerve Injury.
Chung YF, Chen JH, Li CW, Hsu HY, Chen YP, Wang CC, Chiu IM. Chung YF, et al. Int J Mol Sci. 2022 Jun 23;23(13):7002. doi: 10.3390/ijms23137002. Int J Mol Sci. 2022. PMID: 35806005 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous