Beta-amyloid (25-35) peptide and IFN-gamma synergistically induce the production of the chemotactic cytokine MCP-1/JE in monocytes and microglial cells.
The molecular mechanisms involved in the development of senile plaques characteristic of aging and Alzheimer's disease are poorly understood. In this study, we examined whether human monocytes and murine microglial cells stimulated with the active fragment of amyloid beta-protein (Abeta(25-35)) express the monocyte chemotactic protein-1 (MCP-1)/JE. We show that upon incubation with Abeta(25-35), human monocytes accumulate MCP-1 mRNA and produce significant amounts of MCP-1. The effect of Abeta(25-35) on MCP-1 secretion was neither mimicked by a scrambled analogue nor affected by polymyxin B sulfate, even though the latter almost completely abolished the effect of LPS on MCP-1 expression. Murine microglial cells stimulated with Abeta(25-35) also expressed high levels of JE mRNA (the murine counterpart of MCP-1) and released bioactive chemotactic factors. In addition, we report that IFN-gamma significantly synergizes with Abeta(25-35) either in human monocytes or in murine microglial cells, and that Abeta(25-35) plus/minus IFN-gamma-mediated early induction of MCP-1 mRNA does not require new protein synthesis. Finally, we provide evidence that the Abeta(25-35)- and Abeta plus IFN-gamma-induced production of MCP-1 is, in large part, mediated in an autocrine fashion by endogenous TNF-alpha. Taken together, our findings uncover another novel biologic action of Abeta(25-35) and might help in better understanding the mechanisms underlying mononuclear phagocyte recruitment and activation into amyloid deposits.
Meda
L
L
Institute of General Pathology, University of Verona, Verona, Italy.
Bernasconi
S
S
Bonaiuto
C
C
Sozzani
S
S
Zhou
D
D
Otvos
L
L
Mantovani
A
A
Rossi
F
F
Cassatella
M A
MA
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011112:Polymyxin B / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D018932:Chemokine CCL2; D016209:Interleukin-8; D010446:Peptide Fragments; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); D007371:Interferon-gamma; D011112:Polymyxin B