Temporal and mechanistic effects of heat shock on LPS-mediated degradation of IkappaBalpha in macrophages |
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Authors: | Grossman Bruce J Shanley Thomas P Odoms Kelli Dunsmore Katherine E Denenberg Alvin G Wong Hector R |
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Institution: | (1) Division of Critical Care Medicine, Children's Hospital Medical Center, and Children's Hospital Research Foundation, Cincinnati, OH, 45229-3039 |
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Abstract: | Previous studies demonstrated important interactions between the heat shock response and the I B /NF- B pathway when these two pathways are induced sequentially. One such interaction involves the ability of heat shock to inhibit subsequent degradation of I B in response to a proinflammatory signal. Herein we investigated the temporal relationship between recovery from heat shock and inhibition of I B degradation, and the proximal mechanisms by which heat shock inhibits degradation of I B in macrophages. In RAW 264.7 murine macrophages, prior heat shock inhibited LPS-mediated I B degradation up to 4 h after recovery from heat shock, and this effect correlated with inhibition of LPS-mediated activation of NF- B. Beyond these recovery periods, heat shock did not inhibit I B degradation. I B kinase (IKK) assays demonstrated that heat shock inhibited LPS-mediated activation of IKK up to 1 h after recovery from heat shock. Heat shock also increased intracellular phosphatase activity, and inhibition of intracellular phosphatase activity partially reversed the ability of heat shock to inhibit both LPS-mediated degradation of I B and LPS-mediated activation of IKK. These data demonstrate that the ability of heat shock to inhibit degradation of I B is dependent on the recovery period between the heat shock stimulus and the proinflammatory stimulus. The mechanism by which heat shock inhibits degradation of I B involves dual modulation of IKK and intracellular phosphatase activity. |
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Keywords: | Signal transduction inflammation NF- B" target="_blank">gif" alt="kappa" align="BASELINE" BORDER="0">B I -kinase" target="_blank">gif" alt="kappa" align="BASELINE" BORDER="0">-kinase phosphatase |
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