Neurotrophic factors regulate cathepsin S in macrophages and microglia: A role in the degradation of myelin basic protein and amyloid beta peptide.
BACKGROUND
Cathepsin S is a member of the family of cysteine lysosomal proteases preferentially expressed in macrophages and microglia and is active after prolonged incubation in neutral pH. Upon activation of macrophages by a number of inflammatory mediators, there is an increase in secreted cathepsin S activity accompanied by a decrease in cellular cathepsin S activity and protein content, as well as a decrease in cathepsin S mRNA. The decrease in cathepsin S mRNA and protein at the cellular level is in contrast to the response observed in some in vivo scenarios.


METHODS
We investigated the effect of basic fibroblast growth factor (bFGF) and nerve growth factor (NGF), two growth factors present during cell injury and inflammation but not known to activate macrophages and microglia, on the expression of cathepsin S, cathepsin B, and cathepsin L mRNAs in these cells, and on cathepsin S activity. We then tested the ability of cathepsin S to degrade myelin basic protein, and amyloid beta peptide at both acidic and neutral pH.


RESULTS
Basic FGF and NGF treatment of macrophages and microglia significantly increased the levels of cathepsin S, B, and L mRNAs (2- to 5-fold). Basic FGF also increased cathepsin S activity intra- and extracellularly. Recombinant human cathepsin S was able to degrade myelin basic protein and monomeric and dimeric amyloid beta peptide at both acidic and neutral pH, as well as to process human amyloid precursor protein generating amyloidogenic fragments.


CONCLUSIONS
These data suggest that bFGF and NGF may be the molecular signals that positively regulate the expression and activity of cysteine lysosomal proteases (cathepsin S in particular) in macrophages and microglia in vivo, and that there is an interplay between these factors and the activators of inflammation. Disruption of the balance between these two categories of signals may underlie the pathological changes that involve cysteine proteases. http://link.springer-ny.com/link/service/journals/00020/bibs /5n5p334. html
Liuzzo
J P
JP
Department of Pharmacology, New York University Medical Center, New York, New York 10016, USA.
Petanceska
S S
SS
Devi
L A
LA
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002401:Cathepsin B / Q000235:genetics; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line / Q000378:metabolism; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D004676:Myelin Basic Protein; D009414:Nerve Growth Factors; D016222:Fibroblast Growth Factor 2; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S