title: Adult human microglia secrete cytokines when exposed to neurotoxic prion protein peptide: no intermediary role for prostaglandin E2.
abstract: Prion diseases are characterized by accumulation of protease resistant isoforms of prion protein (termed PrP(SC)), glial activation and neurodegeneration. The time course of PrP deposition, appearance of activated microglia, and of neuronal apoptosis in experimentally-induced prion disease suggests that microglial activation precedes the process of neuronal loss. Activated microglia and inflammatory mediators, including cytokines and prostaglandin E2 (PGE2) co-localize with PrP deposits. In vitro, mouse microglia secrete neurotoxic agents and interleukins (IL)-1 and IL-6, when exposed to synthetic peptides representing the neurotoxic fragment of PrP. In this study, adult human microglia were found to secrete IL-6 and TNF-alpha upon exposure to synthetic fibrillar PrP105-132, the putative transmembrane domain of PrP. Little cytokine release occurred following exposure of microglia to C-terminally amidated, nonfibrillar PrP105-132, suggesting that the degree of fibrillarity of PrP peptides affects their biological properties. Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to exert beneficial effects in neurodegenerative disorders through suppressive effects on microglial activation and on cyclooxygenase (COX) activity. Since microglial COX-2 expression and PGE(2) synthesis are increased in human and experimental prion diseases, we investigated the effects of the NSAIDs indomethacin and BF389, an experimental COX-2 selective inhibitor, on the PrP105-132-induced microglial IL-6 and TNF-alpha synthesis in vitro. No inhibitory effects of the NSAIDs were observed. Furthermore, PrP105-132 did not stimulate microglial PGE(2) synthesis. We conclude that, unlike IL-1beta-induced IL-6 synthesis in astrocytes, the PrP-induced IL-6 synthesis in human adult microglia is not PGE2 mediated.
authors.affiliation: Research Institute Neurosciences Vrije Universiteit, Department of Psychiatry, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. r.veerhuis@vumc.nl
authors.forename: Robert
authors.initials: R
authors.lastname: Veerhuis
authors.forename: Jeroen J M
authors.initials: JJ
authors.lastname: Hoozemans
authors.forename: Ingrid
authors.initials: I
authors.lastname: Janssen
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Boshuizen
authors.forename: Jan P M
authors.initials: JP
authors.lastname: Langeveld
authors.forename: Piet
authors.initials: P
authors.lastname: Eikelenboom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008875:Middle Aged; D010078:Oxazines / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000633:toxicity*; D010636:Phenols / Q000494:pharmacology; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000138:chemical synthesis / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D015850:Interleukin-6; D007527:Isoenzymes; D008565:Membrane Proteins; D010078:Oxazines; D010446:Peptide Fragments; D010636:Phenols; D011328:Prions; D014409:Tumor Necrosis Factor-alpha; C419707:prion protein (105-132); C072260:Biofor 389; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin