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The recently discovered cytokine interleukin (IL)-12 is a heterodimeric protein of two disulfide-bonded subunits of 35 and 40 kDa. IL-12 has multiple effects on T cells and natural killer (NK) cells. In particular it appears to be a major factor for the development of cellular immunity. So far activity of the single subunits alone has not been described, however their expression is regulated independently. In this report we demonstrate for the first time that the mouse IL-12 subunit p40 (IL-12p40) specifically antagonizes the effects of the IL-12 heterodimer in different assay systems. The proliferation of mouse splenocytes activated by phorbol ester and IL-12 was inhibited by IL-12p40, whereas the proliferation induced by phorbol ester and IL-2 was not affected. Furthermore, the synthesis of interferon (IFN)-gamma by mouse splenocytes activated with IL-2 and IL-12 was suppressed by IL-12p40. Purified mouse splenic CD4+ T cells produced IFN-gamma upon activation with plate-bound anti-CD3 monoclonal antibody which was enhanced more than tenfold in the presence of IL-12. In this system IL-12p40 inhibited only the enhancement caused by IL-12 but not IFN-gamma synthesis of CD4+ T cells stimulated with anti-CD3 alone. Moreover, IL-12p40 inhibited the effects of IL-12 on differentiated T helper type 1 (Th1) cells. IFN-gamma production by Th1 cells induced in a T cell receptor-independent way by macrophages and IL-2 or macrophages and IL-12 was greatly reduced by IL-12p40 providing evidence for the endogenous synthesis of IL-12 in the Th1 cell, macrophage and IL-2 co-cultures. The specificity of inhibition was clearly demonstrated in the homotypic aggregation assay of Th1 cells. Incubation of Th1 cells with either IL-2 and IL-12 or IL-2 and tumor necrosis factor induces LFA-1/ICAM-1-dependent aggregation. Only IL-2 + IL-12 but not IL-2 + tumor necrosis factor-induced aggregation was inhibited in a dose-dependent manner by IL-12p40. Thus, the IL-12 subunit p40 appears to be a specific inhibitor for the IL-12 heterodimer.
F Mattner, and
S Fischer, and
S Guckes, and
S Jin, and
H Kaulen, and
E Schmitt, and
E Rüde, and
T Germann
December 1997,
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F Mattner, and
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S Jin, and
H Kaulen, and
E Schmitt, and
E Rüde, and
T Germann
May 1996,
Mammalian genome : official journal of the International Mammalian Genome Society,
F Mattner, and
S Fischer, and
S Guckes, and
S Jin, and
H Kaulen, and
E Schmitt, and
E Rüde, and
T Germann
January 2006,
Immunology,
F Mattner, and
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S Guckes, and
S Jin, and
H Kaulen, and
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T Germann
February 2000,
European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics,
F Mattner, and
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H Kaulen, and
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E Rüde, and
T Germann
October 2008,
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F Mattner, and
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H Kaulen, and
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T Germann
June 1996,
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F Mattner, and
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T Germann
October 1995,
Immunology today,
F Mattner, and
S Fischer, and
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S Jin, and
H Kaulen, and
E Schmitt, and
E Rüde, and
T Germann
March 2013,
The Journal of biological chemistry,
F Mattner, and
S Fischer, and
S Guckes, and
S Jin, and
H Kaulen, and
E Schmitt, and
E Rüde, and
T Germann
January 2006,
Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban,
F Mattner, and
S Fischer, and
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S Jin, and
H Kaulen, and
E Schmitt, and
E Rüde, and
T Germann
December 2010,
Hybridoma (2005),
