Klinke David J
Department of Chemical Engineering, West Virginia University, Morgantown WV 26506-6102, USA.
J Theor Biol. 2006 May 21;240(2):323-35. doi: 10.1016/j.jtbi.2005.09.022. Epub 2006 Jan 30.
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, we 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, we 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.
白细胞介素-12（IL-12）是一种75千道尔顿的异二聚体（IL12p70），由独立调控的通过二硫键连接的40千道尔顿（p40）和35千道尔顿（p35）亚基组成。p40亚基以单体（IL12p40）或二聚体（IL12(p40)2）的形式存在于细胞外，并且能够拮抗IL12p70的作用。鉴于文献中对于IL12p70、IL12p40和IL12(p40)2的生理作用存在分歧，我们探究了IL-12的生物活性是否仅取决于IL12p70亚基的浓度，或者IL12p70、IL12p40和IL12(p40)2的相对浓度以及它们与IL-12受体的竞争性结合对于在模拟人体生理条件下确定IL-12生物活性是否至关重要。通过纳入成熟人树突状细胞（DC）产生IL12p70、IL12p40和IL12(p40)2以及这些物质与IL-12受体的相互作用，创建了一个关于IL-12生物活性的数学模型。利用该模型，我们探究了γ干扰素（IFN-γ）、白细胞介素-4（IL-4）和前列腺素E2（PGE2）浓度对IL-12生物活性的影响。模拟结果表明，仅IL12p70的浓度并不能指示IL-12的生物活性；相反，成熟DC产生的IL-12的生物活性取决于IL12p70、IL12p40和IL12(p40)2的产生以及它们与IL-12受体的竞争性相互作用。除了通常测量的总p40（IL12p40 + IL12(p40)2）和IL12p70的量之外，IL12p40与IL12(p40)2的比率是IL-12生物活性的一个同样重要但报道不足的决定因素。
