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Inhibition of LPS-induced Cytokines by Bcl-x_L in a Murine Macrophage Cell Line¹

Viktor Lakics^2,*, Andrei E. Medvedev^2,*, Seiji Okada and Stefanie N. Vogel^3,*

^* Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and Department of Developmental Genetics, Chiba University Graduate School of Medicine, Chiba, Japan

The antiapoptotic molecule Bcl-x_L has been implicated in the differentiation and survival of activated macrophages in inflammatory conditions. In this report, the role of Bcl-x_L in LPS-induced cytokine gene expression and secretion was studied. Bcl-x_L-transfected RAW 264 macrophages were protected from gliotoxin-induced apoptosis, indicating the presence of functional Bcl-x_L. Overexpression of Bcl-x_L in this macrophage cell line was also associated with a marked inhibition of LPS-induced TNF-, JE/monocyte chemoattractant protein 1, and macrophage inflammatory protein 2 secretion. Inhibition of LPS-induced cytokine secretion was paralleled by a decrease in levels of steady-state mRNA for the above cytokines and for IL-1ß. Decreased production of TNF- in Bcl-x_L transfectants was not due to increased mRNA degradation, as the mRNA half-lives were the same in Bcl-x_L transfectants and control macrophages. Although the composition of NF-B complexes detected by EMSA and supershift analysis in nuclear lysates derived from Bcl-x_L transfectants and control cells was indistinguishable, LPS-induced inhibitory B degradation, as well as NF-B binding and AP-1 activation, were slightly decreased by ectopic expression of Bcl-x_L. More strikingly, LPS-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was strongly repressed by Bcl-x_L overexpression, offering a possible mechanism for the inhibition of LPS-induced cytokine production. These data provide the first evidence for a novel role for Bcl-x_L as an anti-inflammatory mediator in macrophages.

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