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Free Content Induction of lymphotoxin-α by interleukin-12 p40 homodimer, the so-called biologically inactive molecule, but not IL-12 p70

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Interleukin-12 (IL-12) p70 (p40:p35) is a bioactive cytokine and its biological functions are becoming clear. On the other hand, the IL-12 p40 homodimer (p402) was considered an inactive or inhibitory molecule and its functions are poorly understood. It has been reported that increased expression of lymphotoxin-α (Lt-α) in the central nervous system as well as in peripheral immune cells is associated with multiple sclerosis and experimental allergic encephalomyelitis. Here we describe that p402 induces the expression of Lt-α in primary mouse and human microglia, BV-2 microglial cells, splenic macrophages, RAW 264.7 cells and splenic T cells. Interestingly, IL-12 p70 was either unable to induce Lt-α or was a very weak inducer of Lt-α in these cell types. Consistently, p402, but not p70, induced Lt-α promoter-driven luciferase activity in microglial cells. Among various stimuli tested, p402 emerged as the most potent followed by IL-16, lipopolyaccharide and double-stranded RNA in inducing the activation of Lt-α promoter in microglial cells. Furthermore, an increase in Lt-α messenger RNA expression by overexpression of p40, but not p35, complementary DNA and induction of Lt-α expression by p402 in microglia isolated from IL-12p35−/− mice confirm that p40, but not p35, is responsible for the induction of Lt-α. Finally, by using primary microglia from IUL-12 receptor β1 deficient (IL-12Rβ1−/−) and IL-12Rβ2−/− mice, we demonstrate that p402 induced the expression of Lt-α in microglia and macrophages via IL-12Rβ1, but not IL-12Rβ2. These studies delineate a novel biological function of p402 that is absent in IL-12.
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Keywords: interleukin-12; interleukin-12 p40 homodimer; interleukin-12 receptor β1; interleukin-12 receptor β2; lymphotoxin-α

Document Type: Research Article

Publication date: July 1, 2009

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