ENHANCEMENT OF BETA-AMYLOID PRECURSOR PROTEIN TRANSCRIPTION AND EXPRESSION BY THE SOLUBLE INTERLEUKIN-6 RECEPTOR INTERLEUKIN-6 COMPLEX

We investigated a potential role for the soluble interleukin-6 recepto r (slL-6R) in modulating interleukin-6 (IL-6) function in the central nervous system by assessing IL-6 and slL-6R effects on beta-amyloid pr ecursor protein (beta-APP) transcription and expression in cells of hu man neuronal origin. Cells transfected with a luciferase reporter plas mid containing a 3.8 kb DNA fragment of the beta-APP promoter were sho wn to have inducible promoter activity when treated with phorbol ester or basic fibroblast growth factor, but not when treated with lipopoly saccharide or IL-6, PCR amplification analysis revealed the presence o f mRNA encoding the signaling subunit of the IL-6 receptor complex, th e gp130 subunit, at levels approximating that found in human cortical tissue. The mRNA encoding the IL-6 receptor, however, was poorly expre ssed and was detectable only at high amplification cycles. When purifi ed sIL-6R protein was added together with IL-6, there was a rapid indu ction of promoter activity within 2 h of stimulation followed by eleva tions in protein levels of both cell-associated and secreted beta-APP. Analysis of mRNA transcripts from human cortical brain tissue and cel l cultures derived from fetal human brain demonstrated the presence of an alternatively spliced secreted form of the IL-6 receptor mRNA, sug gesting that cells of the central nervous system may themselves be a s ource of sIL-6R protein. The capacity for sIL-6R to enhance IL-6 funct ion and broaden the IL-6 target cell population in the brain has impli cations for the regulation of beta-APP expression in disease states su ch as Alzheimer's disease where elevations in brain IL-6 levels have b een reported. (C) 1998 Elsevier Science B.V.