Selective Neutralization of IL-12 P40 Monomer Induces Death in Prostate Cancer Cells Via IL-12-IFN-γ

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2017 Oct 27

PMID 29073075

Citations 27

Authors

Madhuchhanda Kundu

Avik Roy

Kalipada Pahan

Affiliations

Soon will be listed here.

Abstract

Cancer cells are adept at evading cell death, but the underlying mechanisms are poorly understood. IL-12 plays a critical role in the early inflammatory response to infection and in the generation of T-helper type 1 cells, favoring cell-mediated immunity. IL-12 is composed of two different subunits, p40 and p35. This study underlines the importance of IL-12 p40 monomer (p40) in helping cancer cells to escape cell death. We found that different mouse and human cancer cells produced greater levels of p40 than p40 homodimer (p40), IL-12, or IL-23. Similarly, the serum level of p40 was much greater in patients with prostate cancer than in healthy control subjects. Selective neutralization of p40, but not p40, by mAb stimulated death in different cancer cells in vitro and in vivo in a tumor model. Interestingly, p40 was involved in the arrest of IL-12 receptor (IL-12R) IL-12Rβ1, but not IL-12Rβ2, in the membrane, and that p40 neutralization induced the internalization of IL-12Rβ1 via caveolin and caused cancer cell death via the IL-12-IFN-γ pathway. These studies identify a role of p40 monomer in helping cancer cells to escape cell death via suppression of IL-12Rβ1 internalization.

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References

Sharma M, Sharma S, Roy S, Varma S, Bose M . Pulmonary epithelial cells are a source of interferon-gamma in response to Mycobacterium tuberculosis infection. Immunol Cell Biol. 2007; 85(3):229-37. DOI: 10.1038/sj.icb.7100037. View

Trinchieri G . Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995; 13:251-76. DOI: 10.1146/annurev.iy.13.040195.001343. View

Mondal S, Roy A, Pahan K . Functional blocking monoclonal antibodies against IL-12p40 homodimer inhibit adoptive transfer of experimental allergic encephalomyelitis. J Immunol. 2009; 182(8):5013-23. PMC: 2721330. DOI: 10.4049/jimmunol.0801734. View

Pahan K, Sheikh F, Liu X, Hilger S, McKinney M, Petro T . Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells. J Biol Chem. 2000; 276(11):7899-905. PMC: 2041874. DOI: 10.1074/jbc.M008262200. View

Jana M, Dasgupta S, Pal U, Pahan K . IL-12 p40 homodimer, the so-called biologically inactive molecule, induces nitric oxide synthase in microglia via IL-12R beta 1. Glia. 2009; 57(14):1553-65. PMC: 2744843. DOI: 10.1002/glia.20869. View

Sato T, Mizue Terai , Tamura Y, Alexeev V, Mastrangelo M, Selvan S . Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res. 2011; 51(2-3):170-82. DOI: 10.1007/s12026-011-8262-6. View

Rouabhia M, Ross G, Page N, Chakir J . Interleukin-18 and gamma interferon production by oral epithelial cells in response to exposure to Candida albicans or lipopolysaccharide stimulation. Infect Immun. 2002; 70(12):7073-80. PMC: 133048. DOI: 10.1128/IAI.70.12.7073-7080.2002. View

Dasgupta S, Bandopadhyay M, Pahan K . Generation of functional blocking monoclonal antibodies against mouse interleukin-12 p40 homodimer and monomer. Hybridoma (Larchmt). 2008; 27(3):141-51. PMC: 2673812. DOI: 10.1089/hyb.2007.0560. View

Cherwinski H, Schumacher J, Brown K, Mosmann T . Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987; 166(5):1229-44. PMC: 2189643. DOI: 10.1084/jem.166.5.1229. View

10.

Trinchieri G . Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994; 84(12):4008-27. View

11.

Ngiow S, Teng M, Smyth M . A balance of interleukin-12 and -23 in cancer. Trends Immunol. 2013; 34(11):548-55. DOI: 10.1016/j.it.2013.07.004. View

12.

Schroder K, Hertzog P, Ravasi T, Hume D . Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2003; 75(2):163-89. DOI: 10.1189/jlb.0603252. View

13.

Selleck W, Canfield S, Hassen W, Meseck M, Kuzmin A, Eisensmith R . IFN-gamma sensitization of prostate cancer cells to Fas-mediated death: a gene therapy approach. Mol Ther. 2003; 7(2):185-92. DOI: 10.1016/s1525-0016(02)00040-0. View

14.

Brahmachari S, Pahan K . Suppression of regulatory T cells by IL-12p40 homodimer via nitric oxide. J Immunol. 2009; 183(3):2045-58. PMC: 2713791. DOI: 10.4049/jimmunol.0800276. View

15.

Tripp C, Wolf S, UNANUE E . Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993; 90(8):3725-9. PMC: 46374. DOI: 10.1073/pnas.90.8.3725. View

16.

Corbett G, Roy A, Pahan K . Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense. J Immunol. 2012; 189(2):1002-13. PMC: 3523125. DOI: 10.4049/jimmunol.1102624. View

17.

Fenton M, Vermeulen M, Kim S, Burdick M, Strieter R, Kornfeld H . Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis. Infect Immun. 1997; 65(12):5149-56. PMC: 175742. DOI: 10.1128/iai.65.12.5149-5156.1997. View

18.

Jana M, Pahan K . Induction of lymphotoxin-alpha by interleukin-12 p40 homodimer, the so-called biologically inactive molecule, but not IL-12 p70. Immunology. 2008; 127(3):312-25. PMC: 2712100. DOI: 10.1111/j.1365-2567.2008.02985.x. View

19.

Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I . Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science. 1997; 278(5343):1623-6. DOI: 10.1126/science.278.5343.1623. View

20.

Zitvogel L, Tahara H, Robbins P, Storkus W, Clarke M, Nalesnik M . Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts. J Immunol. 1995; 155(3):1393-403. View