Identification of extra- and intracellular alanyl aminopeptidases as new targets to modulate keratinocyte growth and differentiation.
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.
Thielitz
Anja
A
Department of Dermatology and Venereology, IMTM, Leipziger Str. 44, 39120 Magdeburg, Germany. Anja.Thielitz@medizin.uni-magdeburg.de
Bukowska
A
A
Wolke
C
C
Vetter
Robert
R
Lendeckel
Uwe
U
Wrenger
Sabine
S
Hashimoto
Yuichi
Y
Ansorge
Siegfried
S
Gollnick
Harald
H
Reinhold
Dirk
D
D000818:Animals; D001483:Base Sequence; D018826:CD13 Antigens / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D011565:Psoriasis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D004247:DNA; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex; C010531:actinonin