The Bioactivity of Il-12: There's More to the Story Than P70 or P40

David Klinke, Department of Chemical Engineering, West Virginia University, P.O. Box 6102, Morgantown, WV 26506-6102

Mature Dendritic Cells (DC) are some of the most prolific producers of IL-12, a major regulatory cytokine of the adaptive immune response. The term IL-12 is typically used to refer to a collection of IL-12 related proteins. The bioactive form of IL-12 is a 75 kDa heterodimer (IL12p70) comprised of independently-regulated disulfide-linked 40 kDa (p40) and 35 kDa (p35) subunits. The p40 subunit exists extracellularly as a monomer (IL12p40) or dimer (IL12(p40)2) and can antagonize the action of IL12p70. Given the disagreement in the literature over the physiologic roles for IL12p70, IL12p40, and IL12(p40))2, I asked whether the bioactivity of IL-12 depended only on the concentration of the IL12p70 subunit alone or whether the relative concentrations of IL12p70, IL12p40, and IL12(p40))2 and their competitive binding with the IL-12 receptor are essential for determining IL-12 bioactivity under simulated human physiologic conditions. A mathematical model for IL-12 bioactivity was created by incorporating the production of IL12p70, IL12p40, and IL12(p40))2 by mature human DC and the interaction of these species with the IL-12 receptor. Using this model, I explored the effects of IFN-gamma, IL-4, and PGE2 concentrations on the bioactivity of IL-12. The simulations suggest that the concentration of IL12p70 alone is not indicative of IL-12 bioactivity; rather, the bioactivity of IL-12 produced by mature DC depends on IL12p70, IL12p40, and IL12(p40))2 production and their competitive interaction with the IL-12 receptor. In addition to the typically measured quantities of total p40 (IL12p40 + IL12(p40))2) and IL12p70, the ratio of IL12p40 to IL12(p40))2 is an equally important, yet underreported, determinant of IL-12 bioactivity.