Proteasome inactivation promotes p38 mitogen-activated protein kinase-dependent phosphatidylinositol 3-kinase activation and increases interleukin-8 production in retinal pigment epithelial cells.

Paradigms and Technologies
Medicinal Chemistry

Abstract

Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. We have demonstrated previously that oxidative inactivation of the proteasome is a molecular link between oxidative stress and overexpression of interleukin (IL)-8. Here, we elucidated a novel signaling cascade that leads to up-regulation of IL-8 in response to proteasome inactivation. The sequence of events in this cascade includes proteasome inactivation, activation of mitogen-activated protein kinase kinase (MKK)3/MKK6, activation of p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor phosphorylation, phosphatidylinositol 3-kinase (PI3K) activation and increased IL-8 expression. Blocking any of these signaling pathways abolished the up-regulation of IL-8 induced by proteasome inhibition. Although Akt is also activated in response to proteasome inactivation, we found that the PI3K-dependent up-regulation of IL-8 is independent of 3-phosphoinositide-dependent protein kinase (PDK)1 and Akt. Inhibition of PDK1 and Akt with chemical inhibitors or expression of constitutive active Akt had little effects on IL-8 expression in response to proteasome inactivation. In contrast, inhibition of interleukin 2-inducible T cell kinase, a kinase downstream of PI3K, significantly reduced the expression and secretion of IL-8 in response to proteasome inactivation. Together, these data elucidate a novel signaling network that leads to increased IL-8 production in response to proteasome inactivation.

Authors

Fernandes, Alexandre F; Bian, Qingning; Jiang, Jian-Kang; Thomas, Craig; Taylor, Allen; Pereira, Paulo; Shang, Fu;

Keywords

  • Animals
  • Cell Line
  • Enzyme Activation
  • Epithelial Cells/ cytology
  • Epithelial Cells/ metabolism
  • Humans
  • Interleukin-8/ metabolism
  • MAP Kinase Kinase 3/ metabolism
  • MAP Kinase Kinase 6/ metabolism
  • Phosphatidylinositol 3-Kinases/ metabolism
  • Proteasome Endopeptidase Complex/ metabolism
  • Proteasome Inhibitors
  • Protein-Tyrosine Kinases/ metabolism
  • Proto-Oncogene Proteins c-akt/ metabolism
  • Receptor, Epidermal Growth Factor/ metabolism
  • Retinal Pigment Epithelium/ cytology
  • Signal Transduction/ physiology
  • p38 Mitogen-Activated Protein Kinases/ metabolism

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