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J. Biol. Chem., Vol. 283, Issue 30, 20745-20753, July 25, 2008

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Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

A POTENTIAL LINK BETWEEN OXIDATIVE STRESS AND UP-REGULATION OF INTERLEUKIN-8^*

Alexandre F. Fernandes¹, Jilin Zhou^¶, Xinyu Zhang, Qingning Bian, Janet Sparrow^¶, Allen Taylor, Paulo Pereira, and Fu Shang²

From the Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, the Center of Ophthalmology, IBILI, Faculty of Medicine, University of Coimbra, 3000–354 Portugal, and the ^¶Department of Ophthalmology, Columbia University, New York, New York 10032

Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. Stress-induced overproduction of inflammatory cytokines, such as interleukin-8 (IL-8), is one of the early events of inflammation. The objective of this study was to elucidate mechanistic links between oxidative stress and overproduction of IL-8 in retinal pigment epithelial (RPE) cells. We found that exposure of RPE cells to H₂O₂, paraquat, or A2E-mediated photooxidation resulted in increased expression and secretion of IL-8. All of these oxidative stressors also inactivated the proteasome in RPE cells. In contrast, tert-butylhydroperoxide (TBH), a lipophilic oxidant that did not stimulate IL-8 production, also did not inactivate the proteasome. Moreover, prolonged treatment of RPE cells with proteasome-specific inhibitors recapitulated the stimulation of IL-8 production. These data suggest that oxidative inactivation of the proteasome is a potential mechanistic link between oxidative stress and up-regulation of the proinflammatory IL-8. The downstream signaling pathways that govern the production of IL-8 include NF-B and p38 MAPK. Proteasome inhibition both attenuated the activation and delayed the turnoff of NF-B, resulting in biphasic effects on the production of IL-8. Prolonged proteasome inhibition (>2 h) resulted in activation of p38 MAPK via activation of MKK3/6 and increased the production of IL-8. Chemically inhibiting the p38 MAPK blocked the proteasome inhibition-induced up-regulation of IL-8. Together, these data indicate that oxidative inactivation of the proteasome and the related activation of the p38 MAPK pathway provide a potential link between oxidative stress and overproduction of proinflammatory cytokines, such as IL-8.

Received for publication, January 10, 2008 , and in revised form, April 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants EY 11717 (to F. S.), EY 13250 (to A. T.), and EY12951 (to J. R. S.). This work was also supported by Portuguese Foundation for Science and Technology Grant POCI/SAU-OBS/57772/2004 (to P. P.) and United States Department of Agriculture Grant CRIS 1950-51000-060-01A. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Recipient of Portuguese Foundation for Science and Technology Fellowship SFRH/BD/19039/2004.

² To whom correspondence should be addressed: 711 Washington St., Boston, MA 02111. Tel.: 617-556-3158; Fax: 617-556-3132; E-mail: fu.shang{at}tufts.edu.

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