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MBC in Press, published online ahead of print July 1, 2009
Mol. Biol. Cell 10.1091/mbc.E08-10-1068

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Submitted on October 27, 2008
Revised on June 1, 2009
Accepted on June 19, 2009

Proteasome Inactivation Promotes p38 MAPK-dependent PI3K Activation and Increases IL-8 Production in Retinal Pigment Epithelial Cells

Alexandre F. Fernandes,*{dagger} Qingning Bian,* Jian-Kang Jiang,{ddagger} Craig J. Thomas,{ddagger} Allen Taylor,* Paulo Pereira,{dagger} and Fu Shang*

*Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111; {dagger}Centre of Ophthalmology, IBILI – Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; {ddagger}Chemical Genomics Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892-3370

Monitoring Editor: William P. Tansey

Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. We have previously demonstrated that oxidative inactivation of the proteasome is a molecular link between oxidative stress and overexpression of 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 MKK3/MKK6, activation of p38 MAPK, EGFR phosphorylation, 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 PDK1 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 Itk, 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.

Address correspondence to: Fu Shang (fu.shang{at}tufts.edu)






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