cct018159 and Necrosis

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.

Topics: Animals; Anti-Inflammatory Agents; Benzoquinones; Cell Line; Chemokine CCL2; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Heterocyclic Compounds, 2-Ring; HSP90 Heat-Shock Proteins; Humans; Inflammation Mediators; Interleukin-1beta; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lactams, Macrocyclic; Lipopolysaccharides; Male; Necrosis; Permeability; Protein Kinase Inhibitors; Pyrazoles; Rats; Rats, Inbred Lew; Retinal Pigment Epithelium; Signal Transduction; Time Factors; Tumor Necrosis Factor-alpha; Uveitis