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Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis

Vassiliki Poulaki^*, Eirini Iliaki^*, Nicholas Mitsiades, Constantine S. Mitsiades, Yiannis N. Paulus^*, Deisy V. Bula^*, Evangelos S. Gragoudas^* and Joan W. Miller^*,1

^* Angiogenesis/Laser Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA; and

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

¹Correspondence: Angiogenesis/Laser Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles St., Boston, MA 02114, USA. E-mail: jwmiller{at}meei.harvard.edu

Heat shock protein (Hsp) 90 inhibitors, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), constitute promising novel therapeutic agents. We investigated the anti-inflammatory activity of 17-AAG in endotoxin-induced uveitis (EIU) in rats. After the induction of EIU with a footpad injection of lipopolysaccharide (LPS), female Lewis rats received a single intraperitoneal. (i.p.) injection of 17-AAG or vehicle. Twenty-four hours later, the retinas were extracted and assayed for leukocyte adhesion; blood-retinal barrier breakdown; VEGF, TNF-, IL-1ß, and CD14 protein levels; NF-B and HIF-1 activity; hsp90 and 70 levels and expression and phosphorylation of the tight junction proteins ZO-1 and occludin. 17-AAG treatment significantly suppressed the LPS-induced increase in retinal leukocyte adhesion; vascular leakage; NF-B, HIF-1, p38, and PI-3K activity; and VEGF, TNF-, and IL-1ß levels. 17-AAG also suppressed phosphorylation of ZO-1 and occludin by inhibiting their association with p38 and PI-3K. Although 17-AAG treatment did not reduce the LPS-induced increase in total CD14 levels in leukocytes, it significantly decreased membrane CD14 levels. These data suggest that Hsp90 inhibition suppresses several cardinal manifestations of endotoxin-induced uveitis in the rat. 17-AAG has demonstrated a favorable safety profile in clinical trials in cancer patients and represents a promising therapeutic agent for the treatment of inflammatory eye diseases.—Poulaki, V., Iliaki, E., Mitsiades, N., Mitsiades, C. S., Paulus, Y. M., Bula, D. V., Gragoudas, E. S., Miller, J. W. Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis.

Key Words: lipopolysaccharide • EIU • inflammatory eye disease

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