Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis.
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-alpha, IL-1beta, and CD14 protein levels; NF-kappaB and HIF-1alpha 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-kappaB, HIF-1alpha, p38, and PI-3K activity; and VEGF, TNF-alpha, and IL-1beta 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
Vassiliki
V
Angiogenesis/Laser Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles St., Boston, MA 02114, USA.
Iliaki
Eirini
E
Mitsiades
Nicholas
N
Mitsiades
Constantine S
CS
Paulus
Yiannis N
YN
Bula
Deisy V
DV
Gragoudas
Evangelos S
ES
Miller
Joan W
JW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000633:toxicity; D016227:Benzoquinones / Q000627:therapeutic use*; D001813:Blood-Retinal Barrier / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D004731:Endotoxins / Q000633:toxicity; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000097:blood; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D007962:Leukocytes / Q000737:chemistry; D018921:Leukostasis / Q000209:etiology / Q000517:prevention & control; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D062793:Occludin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D031300:Retinal Vasculitis / Q000139:chemically induced / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects; D014606:Uveitis, Anterior / Q000139:chemically induced / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000097:blood; D062826:Zonula Occludens-1 Protein; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001427:Bacterial Toxins; D016227:Benzoquinones; D004731:Endotoxins; D018841:HSP90 Heat-Shock Proteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D047029:Lactams, Macrocyclic; D018950:Lipopolysaccharide Receptors; D008565:Membrane Proteins; D016328:NF-kappa B; D062793:Occludin; C568987:Ocln protein, rat; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; C027952:salmonella toxin; C467498:vascular endothelial growth factor A, rat; C112765:tanespimycin; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases