Inhibition of RPE cell sterile inflammatory responses and endotoxin-induced uveitis by a cell-impermeable HSP90 inhibitor.
Dying cells release pro-inflammatory molecules, functioning as cytokines to trigger cell/tissue inflammation that is relevant to disease pathology. Heat-shock protein 90 (HSP90) is believed to act as a danger signal for tissue damage once released extracellularly. Potential roles of HSP90 were explored in retinal pigment epithelial (RPE) inflammatory responses to necrosis. Cellular extracts can trigger ARPE-19 cell inflammatory responses, producing cytokines that lead to an increase in ARPE-19 cell monolayer permeability. Addition of recombinant HSP90β mimics the induction of chemokines IL-8 and MCP-1 in cultured RPE cells, suggesting that released HSP90 can incite RPE cell sterile inflammatory responses. Consistent with this, classical HSP90 inhibitors were shown to substantially reduce necrosis-induced cytokine production and permeability increases in ARPE-19 cells. Moreover, a cell-impermeable inhibitor, 17-N,N-dimethylaminoethylamino-17-demethoxy-geldanamycin-N-oxide, also efficiently inhibited necrosis-induced cytokine production and TNF-α/IL-1β-induced increase in ARPE-19 cell permeability in vitro and endotoxin-induced development of uveitis in vivo, suggesting that HSP90 can contribute to necrosis-induced RPE inflammatory responses. Collectively, our data identify HSP90 as a pro-inflammatory molecule in RPE cell sterile inflammatory responses.
Retinal Disease Research, Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA. qin_suofu@allergan.com
Suofu
S
Qin
Ming
M
Ni
Xiuyun
X
Wang
Florence
F
Maurier-Mahé
Dixie-Lee
DL
Shurland
Gerard A
GA
Rodrigues
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D009336:Necrosis; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; C111835:CCL2 protein, human; C506244:CCT018159; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; C493165:HSP90AB1 protein, human; D006574:Heterocyclic Compounds, 2-Ring; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016209:Interleukin-8; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; C112765:tanespimycin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases