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Rapid Externalization of 27-kDa Heat Shock Protein (HSP27) and Atypical Cell Death in Neutrophils Treated With the Sphingolipid Analog Drug FTY720

Rapid Externalization of 27-kDa Heat Shock Protein (HSP27) and Atypical Cell Death in Neutrophils Treated With the Sphingolipid Analog Drug FTY720

Joanna Skrzeczyńska-Moncznik, Małgorzata Bzowska, Anna Nogieć, Agnieszka Sroka, Mirosław Zarębski, Luc Vallières, Krzysztof Guzik

J Leukoc Biol. 2015 Oct;98(4):591-9.

PMID: 26216939

Abstract:

The sphingolipid analog fingolimod is known to induce apoptosis of tumor cells and lymphocytes. Its effect on neutrophils has not been investigated so far. Here, we describe a fingolimod-induced atypical cell death mechanism in human neutrophils, characterized by rapid translocation of heat shock protein 27 to the cell surface, extensive cell swelling and vacuolization, atypical chromatin staining and nuclear morphology, and phosphorylation of mixed lineage kinase domain-like protein. Fingolimod also induces typical apoptotic features, including rapid externalization of phosphatidylserine and activation of caspase-8. Fingolimod-induced neutrophil death is independent of sphingosine-1-phosphate receptors and positively regulated by protein phosphatase A. Externalization of phosphatidylserine and heat shock protein 27 can be partially inhibited by inhibitors of caspase-8 [Z-Ile-Glu(O-Me)-Thr-Asp(O-Me)-fluoromethyl ketone], receptor-interacting protein kinase 1 (necrostatin-1), receptor-interacting protein kinase 3 (necrosulfonamide), and heat shock protein 90 [geldanamycin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin]. Furthermore, NADPH oxidase 1 inhibition with diphenyleneiodonium chloride protects neutrophils against fingolimod-mediated cell death. Overall, these observations suggest that fingolimod acts through a mechanism involving the necrosome signaling complex and the oxidative stress machinery.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR424997	Z-Ile-Glu(O-ME)-Thr-Asp(O-Me) fluoromethyl ketone			Price

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