Heat Shock Pretreatment Influences the Expression of PKC Isoforms during Sepsis

Chen, Hsiang-Wen; Hsu, Chin; Hsu, Hseng‐Kuang; Lu, Tzongshi; Wang, Shu-Jung; Yang, Rei‐Cheng

doi:10.1006/jsre.2001.6273

Cited by 2 publications

(1 citation statement)

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“…In the animal model, a decrease of PKC␣ expression during sepsis has been described also for other cell systems. In hepatocytes PKC␣ depletion causes hepatic failure in sepsis (28) and in lymphocytes PKC␣ expression declines during progression of sepsis in rats (29). To establish a cause-effect relation between down-regulation of PKC␣ in monocytes derived from septic patients and an attenuated oxidative response, we established a cell culture model to mimic desensitized monocytes/macrophages.…”

Section: Discussionmentioning

confidence: 99%

Activation-Induced Depletion of Protein Kinase Cα Provokes Desensitization of Monocytes/Macrophages in Sepsis

Knethen

Tautenhahn

Lindemann

et al. 2005

The Journal of Immunology

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Sepsis accounts for the majority of fatal casualties in critically ill patients, because extensive research failed to significantly improve appropriate therapy strategies. Thus, understanding molecular mechanisms initiating the septic phenotype is important. Symptoms of septic disease are often associated with monocyte/macrophage desensitization. In this study, we provide evidence that a desensitized cellular phenotype is characterized by an attenuated oxidative burst. Inhibition of the oxidative burst and depletion of protein kinase Cα (PKCα) were correlated in septic patients. To prove that PKCα down-regulation indeed attenuated the oxidative burst, we set up a cell culture model to mimic desensitized monocytes/macrophages. We show that LPS/IFN-γ-treatment of RAW264.7 and U937 cells lowered PKCα expression and went on to confirm these data in primary human monocyte-derived macrophages. To establish a role of PKCα in cellular desensitization, we overexpressed PKCα in RAW264.7 and U937 cells and tested for phorbolester-elicited superoxide formation following LPS/IFN-γ-pretreatment. Inhibition of the oxidative burst, i.e., cellular desensitization, was clearly reversed in cells overexpressing PKCα, pointing to PKCα as the major transmitter in eliciting the oxidative burst in monocytes/macrophages. However, PKCα inactivation by transfecting a catalytically inactive PKCα mutant attenuated superoxide formation. We suggest that depletion of PKCα in monocytes from septic patients contributes to cellular desensitization, giving rise to clinical symptoms of sepsis.

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Section: Discussionmentioning

confidence: 99%