Identification of extra- and intracellular alanyl aminopeptidases as new targets to modulate keratinocyte growth and differentiation.

Abstract

Aminopeptidase inhibitors strongly affect proliferation, differentiation, and function of immune cells and show therapeutic potential in inflammatory disorders. In psoriatic lesions, keratinocytes display increased cellular turnover and disturbed differentiation, leading to epidermal hyperplasia accompanied by the loss of stratum granulosum. Here, we report in the HaCaT hyperproliferative keratinocyte cell line as well as in two primary keratinocyte strains in vitro a molecular and biochemical analysis of the expression of both membrane and cytosol alanyl aminopeptidase (cAAP) on the mRNA, protein, and enzymatic activity level. We found a clear dose-dependent suppression of DNA synthesis in vitro in the presence of the inhibitors actinonin, bestatin, and the cAAP-specific inhibitor PAC-22 correlating well with the simultaneous decrease in enzyme activity. In vivo, actinonin dose-dependently restored the stratum granulosum and ameliorated the impaired keratinocyte differentiation in the mouse tail model of psoriasis. Taken together, these data suggest that targeting alanyl aminopeptidases may be beneficial for psoriasis and other inflammatory skin disorders.

• Authors: Anja Thielitz, A Bukowska, C Wolke, Robert Vetter, Uwe Lendeckel, Sabine Wrenger, Yuichi Hashimoto, Siegfried Ansorge, Harald Gollnick, Dirk Reinhold
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 321 Issue 4 Pg. 795-801 (Sep 03 2004) ISSN: 0006-291X [Print] United States
• PMID: 15358097 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Hydroxamic Acids
• RNA, Messenger
• DNA
• CD13 Antigens
• Leucine
• ubenimex
• actinonin

Topics

• Animals
• Base Sequence
• CD13 Antigens (drug effects, genetics, metabolism)
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Cell Line
• Cell Membrane (enzymology)
• Cells, Cultured
• Cytosol (enzymology)
• DNA (biosynthesis)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Humans
• Hydroxamic Acids (pharmacology)
• Keratinocytes (cytology, drug effects, enzymology)
• Leucine (analogs & derivatives, pharmacology)
• Male
• Mice
• Psoriasis (drug therapy, enzymology, pathology)
• RNA, Messenger (genetics, metabolism)