EXPRESSION OF GAMMA-IFN RESPONSIVE GENES IN SCAVENGER RECEPTOR OVER-EXPRESSING MONOCYTES IS ASSOCIATED WITH XANTHOMATOSIS

We have recently described an inherited over-expression of the macroph age scavenger receptor (SR) in blood monocytes from members of a kindr ed, only two of whom displayed extensive xanthomatosis. Using mRNA dif ferential display we demonstrated abnormally high expression of the si gnal transducer and activator of transcription (STAT1 alpha) in monocy tes from the proband II-2. Expression of gamma-interferon inducible pr otein 10 (IP-10), a STAT1 alpha-responsive gene and mediator of inflam matory response, was also abnormally expressed in the monocytes from I I-2. Over-expression of both genes was restricted to monocytes from II -2 and was not observed in monocytes from the clinically unaffected fa mily members, unlike that of SR. Gel retardation assays with THP-1 cel l extracts identified gamma-IFN inducible DNA binding activity to thre e potential STAT1 DNA binding elements in the human IP-10 promoter reg ion from nucleotides -245 to -188. Taken together these results sugges t that gamma-interferon mediated cell activation is responsible for ST AT1 alpha-induced transcription of the IP-10 gene in THP-I macrophages as well as in monocytes from II-2. Analysis of monocytes from familia l hypercholesterolemic (FH) subjects, who frequently develop xanthomat osis, revealed a significant number of subjects with elevated STAT1 al pha and IP-10 expression. Our data suggest that the inflammatory effec ts of gamma-IFN signaling could play a role in foam cell formation and xanthomatosis. (C) 1998 Elsevier Science Ireland Ltd. All rights rese rved.