Inflammatory mediators regulate cathepsin S in macrophages and microglia: A role in attenuating heparan sulfate interactions.
BACKGROUND
Cathepsin S is a member of the family of cysteine lysosomal proteases. The distribution of cathepsin S is restricted to cells from the mononuclear lineage both in the brain and in the periphery. Also, its protease activity is uniquely stable at neutral pH.


METHODS
We compared the expression of cathepsin S, B, and L mRNAs in various undifferentiated and differentiated cells of mononuclear origin, and examined the modulation of these mRNAs by inflammatory mediators (lipopolysaccharide and various cytokines). In addition, the effect of these agents on cathepsin S protein levels and protease activity was also determined. Lastly, the ability of cathepsin S to process basement membrane components such as heparan sulfate proteoglycans in vitro and in vivo was assessed.


RESULTS
Cathepsin S, B, and L mRNAs are expressed in mature macrophages and microglial cells and not in undifferentiated monocytes. Activators of macrophages negatively regulate all three transcripts. Consistent with this, treatment with these agents leads to a decrease in intracellular cathepsin S protein levels and activity. However, the same treatments result in stimulation of secreted cathepsin S activity. Cathepsin S is capable of degrading heparan sulfate proteoglycans in vitro. Also, when expressed in endothelial cells, cathepsin S autocrinely attenuates the basic fibroblast growth factor (bFGF)-mediated binding of FGF receptor containing cells to endothelial cells, by acting on basement membrane proteoglycans.


CONCLUSIONS
Taken together, these data imply that cathepsin S is a regulatable cysteine protease that plays a role in the degradation of extracellular proteins, whose secretion from macrophages and microglia is increased by signals that lead to activation of these cells, and may be important in regulating extracellular matrix interactions. http://link.springer-ny. com/link/service/journals/00020/bibs/5n5p320.html
Liuzzo
J P
JP
Department of Pharmacology, Kaplan Cancer Center, New York University School of Medicine, New York, New York, USA.
Petanceska
S S
SS
Moscatelli
D
D
Devi
L A
LA
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002401:Cathepsin B / Q000235:genetics; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002448:Cell Adhesion; D002460:Cell Line; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D010450:Endopeptidases; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D002401:Cathepsin B; D056668:Cathepsin L; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D010450:Endopeptidases; D016222:Fibroblast Growth Factor 2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D016898:Interferon-alpha; D007371:Interferon-gamma; D007375:Interleukin-1; D007930:Leucine; D008070:Lipopolysaccharides; D011509:Proteoglycans; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C071927:perlecan; C534278:Ctsl protein, mouse; C028217:cathepsin S; C024974:E 64