Sphingosine inhibits phorbol ester-induced inflammation, ornithine decarboxylase activity, and activation of protein kinase C in mouse skin.
Tumor promoting phorbol esters, such as 12-0-tetradecanoylphorbol-13-acetate (TPA), when applied topically to mouse skin cause inflammation and hyperplasia. The major cellular phorbol ester receptor is a calcium and phospholipid dependent protein kinase, protein kinase C (PK-C). PK-C is directly activated by TPA and most of the responses of cells to TPA appear to be mediated by PK-C. This suggests that PK-C may play a key role as a mediator of inflammation and growth in TPA treated mouse skin. Sphingosine has been reported to be a potent inhibitor of PK-C in vitro and in intact leukocytes. We therefore have investigated the effects of sphingosine upon TPA-induced inflammation, hyperplasia, induction of ornithine decarboxylase (ODC) activity and ODC mRNA, and activation of PK-C in mouse skin. The results demonstrate that sphingosine is a potent inhibitor of all of the TPA-induced responses examined. These data are compatible with the hypothesis that PK-C is a major mediator of the phorbol ester response in mouse skin. Furthermore, PK-C inhibitors may have therapeutic potential in inflammatory skin diseases such as psoriasis.
Gupta
A K
AK
Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109.
Fisher
G J
GJ
Elder
J T
JT
Nickoloff
B J
BJ
Voorhees
J J
JJ
D000287:Administration, Topical; D000818:Animals; D003872:Dermatitis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D008812:Mice, Hairless; D065108:Ornithine Decarboxylase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D013110:Sphingosine / Q000008:administration & dosage*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000633:toxicity
D065108:Ornithine Decarboxylase Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011493:Protein Kinase C; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate