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1.  Internalization of Exogenous Cystatin F Supresses Cysteine Proteases and Induces the Accumulation of Single-chain Cathepsin L by Multiple Mechanisms* 
The Journal of Biological Chemistry  2011;286(49):42082-42090.
Background: Cystatin F is a protease inhibitor normally found within the endocytic pathway, but can be secreted.
Results: Secreted cystatin F can be internalized thereby inhibiting multiple targets and causing the accumulation of cathepsin L.
Conclusion: Cystatin F inhibits the CatL convertase AEP and stabilizes CatL protein levels.
Significance: Secreted cystatin F can be activated in trans expanding its inhibitory potential beyond its site of synthesis.
Cystatin F is an unusual member of the cystatin family of protease inhibitors, which is made as an inactive dimer and becomes activated by proteolysis in the endo/lysosome pathway of the immune cells that produce it. However a proportion is secreted and can be taken up and activated by other cells. We show here that cystatin F acquired in this way induces a dramatic accumulation of the single-chain form of cathepsin L (CatL). Cystatin F was observed in the same cellular compartments as CatL and was tightly complexed with CatL as determined by co-precipitation studies. The observed accumulation of single-chain CatL was partly due to cystatin F-mediated inhibition of the putative single-chain to two-chain CatL convertase AEP/legumain and partly to general suppression of cathepsin activity. Thus, cystatin F stabilizes CatL leading to the dramatic accumulation of an inactive complex composed either of the single-chain or two-chain form depending on the capacity of cystatin F to inhibit AEP. Cross-transfer of cystatin F from one cell to another may therefore attenuate potentially harmful effects of excessive CatL activity while paradoxically, inducing accumulation of CatL protein. Finally, we confirmed earlier data (Beers, C., Honey, K., Fink, S., Forbush, K., and Rudensky, A. (2003) J. Exp. Med. 197, 169–179) showing a loss of CatL activity, but not of CatL protein, in macrophages activated with IFNγ. However, we found equivalent loss of CatL activity in wild type and cystatin F-null macrophages suggesting that an inhibitory activity other than cystatin F quenches CatL activity in activated macrophages.
doi:10.1074/jbc.M111.253914
PMCID: PMC3234946  PMID: 21956111
Dendritic Cells; Endocytosis; Lysosomes; Macrophages; Protease; Protease Inhibitor; Cathepsin; Cell Biology; Cystatin; Asparagine Endopeptidase (AEP)
2.  Role of CCL11 in Eosinophilic Lung Disease during Respiratory Syncytial Virus Infection 
Journal of Virology  2005;79(4):2050-2057.
Respiratory syncytial virus (RSV) is a major viral pathogen of infants and the elderly. Significant morbidity is caused by an overexuberant mixed lung cell infiltrate, which is thought to be driven by chemokines. One of the main chemotactic mediators responsible for the movement of eosinophils is CCL11 (eotaxin). Using a mouse model of eosinophilic bronchiolitis induced by RSV, we show here that treatment in vivo with a blocking antibody to CCL11 greatly reduces lung eosinophilia and disease severity. In addition, anti-CCL11 caused a striking inhibition of CD4-T-cell influx and shifted cytokine production away from interleukin-5 without reducing the resistance to viral replication. These results suggest that in addition to influencing eosinophil diapedesis and survival, anti-CCL11 has an action on T cells. These studies strengthen the case for anti-CCL11 treatment of Th2-driven diseases.
doi:10.1128/JVI.79.4.2050-2057.2005
PMCID: PMC546549  PMID: 15681407

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