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* Department of Anatomy and Neurobiology and Research Institute of Natural Science, Gyeongsang National University College of Medicine, Institute of Health Sciences, Jinju, Korea;
Division of Food Science and Biotechnology, College of Agriculture and Life Sciences, Kangwon National University, Chunchon, Korea; and
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Mouse brain microglial cells undergo apoptosis on exposure to inflammatory stimuli, which is considered as an autoregulatory mechanism to control their own activation. Here, we present evidence that an antiproliferative B cell translocation gene 1 (BTG1) constitutes a novel apoptotic pathway of LPS/IFN-
-activated microglia. The expression of BTG1 was synergistically enhanced by LPS and IFN- in BV-2 mouse microglial cells as well as in primary microglia cultures. Levels of BTG1 expression inversely correlated with a proliferative capacity of the microglial cells. Tetracycline-based conditional expression of BTG1 not only suppressed microglial proliferation but also increased the sensitivity of microglial cells to NO-induced apoptosis, suggesting a novel mechanism of cooperation between LPS and IFN- in the induction of microglial apoptosis. An increase in BTG1 expression, however, did not affect microglial production of NO, TNF-
, or IL-1
, indicating that the antiproliferative BTG1 is important in the activation-induced apoptosis of microglia, but not in the activation itself. The synergistic action of LPS and IFN- in the microglial BTG1 induction and apoptosis was dependent on the Janus kinase/STAT1 pathway, but not IFN-regulatory factor-1, as demonstrated by a pharmacological inhibitor of Janus kinase (AG490), STAT1 dominant negative mutant, and IFN-regulatory factor-1-deficient mice. Taken together, antiproliferative BTG1 may participate in the activation-induced cell death of microglia by lowering the threshold for apoptosis; BTG1 increases the sensitivity of microglia to apoptogenic action of autocrine cytotoxic mediator, NO. Our results point out an important link between the proliferative state of microglia and their sensitivity to apoptogenic agents.
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