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Vol. 20, Issue 16, 3690-3699, August 15, 2009

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Proteasome Inactivation Promotes p38 Mitogen-activated Protein Kinase-dependent Phosphatidylinositol 3-kinase Activation and Increases Interleukin-8 Production in Retinal Pigment Epithelial Cells

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

*Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111; Centre of Ophthalmology, Institute of Biomedical Research on Light and Image–Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; and Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3370

Submitted October 27, 2008; Revised June 1, 2009; Accepted June 19, 2009
Monitoring Editor: William P. Tansey

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.

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

Abbreviations used: AP, activator protein; AMD, age-related macular degeneration; AP-1, activator protein-1; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HIF, hypoxia-inducible factor; IL-8, interleukin-8; Itk, interleukin-2–inducible T cell kinase; MAPK, mitogen-activated protein kinase; MKK, mitogen-activated protein kinase kinase; PDGF, platelet-derived growth factor; PDK1, 3-phosphoinositide-dependent protein kinase-1; PI3K, phosphatidylinositol 3-kinase; RPE, retinal pigment epithelial cells; Tec, tyrosine kinase expressed in hepatocellular carcinoma; UPP, ubiquitin–proteasome pathway.