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In vivo production and function of IL-12 p40 homodimers.

F P Heinzel, A M Hujer, F N Ahmed and R M Rerko
J Immunol May 1, 1997, 158 (9) 4381-4388;
F P Heinzel
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A M Hujer
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F N Ahmed
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R M Rerko
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Abstract

The bioactivity of IL-12 is mediated by heterodimers of disulfide-linked p35 and p40 protein subunits. Homodimeric p40 competes with heterodimer for binding to the high affinity IL-12R and inhibits IL-12 bioactivity in vitro. However, the production and significance of p40 homodimer as a cytokine antagonist in vivo have not been determined. In these studies, we observed increased amounts of both IL-12 p40 monomer and homodimer in the serum of C57BL/6 mice following injection of 300 microg of Salmonella enteritidis LPS. Homodimer constituted between 20 and 40% of the total circulating p40 in endotoxemic sera, as confirmed by both Sephacryl S-100 gel filtration and p40-specific immunoprecipitation analyses. Similar relative amounts of homodimer and monomer were observed in endotoxemic BALB/c, C57BL/6, IFN-gamma-deficient C57BL/6 mice and C57BL/6 mice previously infected with bacille Calmette-Guérin. To determine whether IL-12 p40 homodimer was capable of antagonizing IL-12-dependent IFN-gamma responses in vivo, we pretreated C57BL/6 mice with purified rIL-12 p40 homodimer before i.p. challenge with endotoxin. Mice treated with 40 to 80 microg of p40 homodimer generated 80 to 82% less circulating IFN-gamma during acute endotoxemia than saline controls (p < 0.01). We conclude that p40 homodimer is produced in vivo, functions as a cytokine antagonist in the context of the mouse model of acute endotoxemia, and may represent a novel form of self-regulating cytokine response.

  • Copyright © 1997 by American Association of Immunologists

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The Journal of Immunology
Vol. 158, Issue 9
1 May 1997
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In vivo production and function of IL-12 p40 homodimers.
F P Heinzel, A M Hujer, F N Ahmed, R M Rerko
The Journal of Immunology May 1, 1997, 158 (9) 4381-4388;

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In vivo production and function of IL-12 p40 homodimers.
F P Heinzel, A M Hujer, F N Ahmed, R M Rerko
The Journal of Immunology May 1, 1997, 158 (9) 4381-4388;
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Print ISSN 0022-1767        Online ISSN 1550-6606