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Inflammatory Mediators Regulate Cathepsin S in Macrophages and Microglia: A Role in Attenuating Heparan Sulfate Interactions

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Abstract

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.

Materials and 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.

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Acknowledgments

This work was supported in part by National Institute of Health grants NS 26880 and NS K04 1788 (to L. A. D.).

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Authors and Affiliations

  1. Department of Pharmacology Kaplan Cancer Center, New York University School of Medicine, New York, New York, USA

    John P. Liuzzo &  Lakshmi A. Devi

  2. Department of Cell Biology, Kaplan Cancer Center, New York University School of Medicine, New York, New York, USA

    Suzana S. Petanceska

  3. Dementia Research Group, Nathan Kline Institute at New York University, Orangeburg, New York, USA

    David Moscatelli

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  1. John P. Liuzzo
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  4. Lakshmi A. Devi
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Correspondence to Lakshmi A. Devi.

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Liuzzo, J.P., Petanceska, S.S., Moscatelli, D. et al. Inflammatory Mediators Regulate Cathepsin S in Macrophages and Microglia: A Role in Attenuating Heparan Sulfate Interactions. Mol Med 5, 320–333 (1999). https://doi.org/10.1007/BF03402068

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