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Induction of lymphotoxin‐α by interleukin‐12 p40 homodimer, the so‐called biologically inactive molecule, but not IL‐12 p70
Author(s) -
Jana Malabendu,
Pahan Kalipada
Publication year - 2009
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2008.02985.x
Subject(s) - microglia , lymphotoxin , cytokine , immune system , interleukin 12 , biology , microbiology and biotechnology , alpha (finance) , chemistry , immunology , medicine , in vitro , inflammation , cytotoxic t cell , biochemistry , construct validity , nursing , patient satisfaction
Summary 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 (p40 2 ) 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 p40 2 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, p40 2 , but not p70, induced Lt‐α promoter‐driven luciferase activity in microglial cells. Among various stimuli tested, p40 2 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 p40 2 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 p40 2 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 p40 2 that is absent in IL‐12.