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      A selective inhibitor of p38 MAP kinase, SB202190, induced apoptotic cell death of a lipopolysaccharide-treated macrophage-like cell line, J774.1.

      Biochimica et Biophysica Acta
      Amino Acid Sequence, Animals, Apoptosis, drug effects, Caspase 3, Caspases, metabolism, Cell Line, Enzyme Activation, Enzyme Inhibitors, pharmacology, Heat-Shock Proteins, Imidazoles, In Situ Nick-End Labeling, Lipopolysaccharides, Macrophages, cytology, enzymology, Mice, Mitogen-Activated Protein Kinases, antagonists & inhibitors, Neoplasm Proteins, chemistry, Phosphorylation, Pyridines, Signal Transduction, p38 Mitogen-Activated Protein Kinases

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          A selective p38 MAP kinase (p38 MAPK) inhibitor, SB202190, induced apoptotic cell death of a macrophage-like cell line, J774.1, in the presence of lipopolysaccharide (LPS), as judged by DNA nicks revealed by terminal deoxy transferase (TdT)-mediated dUTP nick end labeling (TUNEL), activation of caspase-3, and subsequent release of lactate dehydrogenase. This cytotoxicity was dependent on both LPS and SB202190, and such inhibitors of the upstream LPS-signaling cascade as polymyxin B and TPCK blocked this macrophage cell death. SB202190 suppressed the kinase activity of p38, leading to inhibition of activation of MAPKAPK2 and then the subsequent phosphorylation of hsp27 in LPS-treated macrophages both in vitro and in vivo, but an inactive analog of SB202190, SB202474, did not. There was a threshold of the time of addition of SB202190 to LPS-treated macrophages to induce apoptosis, which was before full transmission of p38 activity to a direct downstream kinase, MAPKAPK2. Besides, localization of phosphorylated hsp27 in Golgi area of the LPS-treated macrophages was suppressed by SB202190, while it was not by SB202474. These results suggest that selective inhibition of p38 MAPK activity in LPS-induced MAP kinase cascade leads to apoptosis of macrophages.

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