Jana Malabendu, Pahan Kalipada
Department of Neurological Sciences, Rush University Medical Center, Cohn Research Building, Suite 320, 1735 West Harrison St., Chicago, IL 60612, United States.
Mol Immunol. 2009 Feb;46(5):773-83. doi: 10.1016/j.molimm.2008.10.033. Epub 2008 Dec 18.
IL-16, a leukocyte chemoattractant factor (LCF), is involved in the disease process of multiple sclerosis and other autoimmune disorders. However, mechanisms by which this LCF is expressed are poorly understood. The present study underlines the importance of IL-12 p40 homodimer (p40(2)), the so-called biologically inactive molecule, in inducing the expression of IL-16 in primary mouse and human microglia, mouse BV-2 microglial cells, mouse peritoneal macrophages, and RAW264.7 cells. In contrast, IL-12 p70, the bioactive heterodimeric cytokine, was unable to induce the expression of IL-16 in any of these cell types. Similarly IL-12 p40(2) also induced the activation of IL-16 promoter in microglia. Among various stimuli tested, p40(2) was the most potent one followed by p40 monomer, IL-16 and IL-23 in inducing the activation of IL-16 promoter in microglial cells. Furthermore, induction of IL-16 mRNA expression by over-expression of p40, but not p35, cDNA and induction of IL-16 expression by p40(2) in microglia isolated from IL-12p35 (-/-) mice confirm that p40, but not p35, is responsible for the induction of IL-16. Finally, by using primary microglia isolated from IL-12Rbeta1 (-/-) and IL-12Rbeta2 (-/-) mice, we demonstrate that p40(2) induces the expression of this LCF via IL-12Rbeta1 but not IL-12Rbeta2. These results delineate a novel biological function of p40(2) and raise the possibility that biological function of IL-12 p40(2) may be different from IL-12 p70.
白细胞介素-16（IL-16）是一种白细胞趋化因子（LCF），参与多发性硬化症和其他自身免疫性疾病的发病过程。然而，这种LCF的表达机制尚不清楚。本研究强调了白细胞介素-12 p40同二聚体（p40(2)），即所谓的无生物学活性分子，在诱导原代小鼠和人小胶质细胞、小鼠BV-2小胶质细胞、小鼠腹腔巨噬细胞和RAW264.7细胞中IL-16表达方面的重要性。相比之下，具有生物活性的异二聚体细胞因子IL-12 p70在这些细胞类型中均无法诱导IL-16的表达。同样，IL-12 p40(2)也能诱导小胶质细胞中IL-16启动子的激活。在测试的各种刺激因素中，p40(2)是诱导小胶质细胞中IL-16启动子激活的最有效因素，其次是p40单体、IL-16和IL-23。此外，p40而非p35的cDNA过表达诱导IL-16 mRNA表达，以及p40(2)在从IL-12p35(-/-)小鼠分离的小胶质细胞中诱导IL-16表达，证实了是p40而非p35负责诱导IL-16。最后，通过使用从IL-12Rβ1(-/-)和IL-12Rβ2(-/-)小鼠分离的原代小胶质细胞，我们证明p40(2)通过IL-12Rβ1而非IL-12Rβ2诱导这种LCF的表达。这些结果描绘了p40(2)的一种新的生物学功能，并增加了IL-12 p40(2)的生物学功能可能不同于IL-12 p70的可能性。
