EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity.
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles in cell activation and proliferation. Many Hsp90 client proteins in tumor cells are mutated or overexpressed oncogenic proteins driving cancer cell growth, leading to the acceptance of Hsp90 as a potential therapeutic target for cancer. Because several signal transduction molecules that are dependent on Hsp90 function are also involved in activation of innate and adaptive cells of the immune system, we investigated the mechanism by which inhibiting Hsp90 leads to therapeutic efficacy in rodent models of inflammation and autoimmunity. EC144, a synthetic Hsp90 inhibitor, blocked LPS-induced TLR4 signaling in RAW 264.7 cells by inhibiting activation of ERK1/2, MEK1/2, JNK, and p38 MAPK but not NF-κB. Ex vivo LPS-stimulated CD11b(+) peritoneal exudate cells from EC144-treated mice were blocked from phosphorylating tumor progression locus 2, MEK1/2, and ERK1/2. Consequently, EC144-treated mice were resistant to LPS administration and had suppressed systemic TNF-α release. Inhibiting Hsp90 also blocked in vitro CD4(+) T cell proliferation in mouse and human MLRs. In vivo, semitherapeutic administration of EC144 blocked disease development in rat collagen-induced arthritis by suppressing the inflammatory response. In a mouse collagen-induced arthritis model, EC144 also suppressed disease development, which correlated with a suppressed Ag-specific Ab response and a block in activation of Ag-specific CD4(+) T cells. Our results describe mechanisms by which blocking Hsp90 function may be applicable to treatment of autoimmune diseases involving inflammation and activation of the adaptive immune response.
Department of Immunobiology, Biogen Idec, San Diego, CA 92122, USA. ted.yun@biogenidec.com
Theodore J
TJ
Yun
Erin K
EK
Harning
Keith
K
Giza
Dania
D
Rabah
Ping
P
Li
Joseph W
JW
Arndt
David
D
Luchetti
Marco A
MA
Biamonte
Jiandong
J
Shi
Karen
K
Lundgren
Anthony
A
Manning
Marilyn R
MR
Kehry
D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
C555354:EC 144; D018841:HSP90 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D011743:Pyrimidines; D011758:Pyrroles