N-acetyl-S-farnesyl-l-cysteine suppresses chemokine production by human dermal microvascular endothelial cells.
Isoprenylcysteine (IPC) molecules modulate G-protein-coupled receptor signalling. The archetype of this class is N-acetyl-S-farnesyl-l-cysteine (AFC). Topical application of AFC locally inhibits skin inflammation and elicitation of contact hypersensitivity in vivo. However, the mechanism of these anti-inflammatory effects is not well understood. Dermal microvascular endothelial cells (ECs) are involved in inflammation, in part, by secreting cytokines that recruit inflammatory cells. We have previously shown that the sympathetic nerve cotransmitter adenosine-5'-triphosphate (ATP) and adenosine-5'-O-(3-thio) triphosphate (ATPγS), an ATP analogue that is resistant to hydrolysis, increase secretion of the chemokines CXCL8 (interleukin-8), CCL2 (monocyte chemotactic protein-1) and CXCL1 (growth-regulated oncogene α) by dermal microvascular ECs. Production of these chemokines can also be induced by the exposure to the proinflammatory cytokine TNFα. We have now demonstrated that AFC dose-dependently inhibits ATP-, ATPγS- and TNFα-induced production of CXCL1, CXCL8 and CCL2 by a human dermal microvascular EC line (HMEC-1) in vitro under conditions that do not affect cell viability. Inhibition of ATPγS- or TNFα-stimulated release of these chemokines was associated with reduced mRNA levels. N-acetyl-S-geranyl-l-cysteine, an IPC analogue that is inactive in inhibiting G-protein-coupled signalling, had greatly reduced ability to suppress stimulated chemokine production. AFC may exert its anti-inflammatory effects through the inhibition of chemokine production by stimulated ECs.
Department of Dermatology, Weill Cornell Medical College, New York, NY 10021, USA.
Katayun
K
Adhami
Jason
J
Lee
Laura
L
Levin
Rachel
R
Moquete
Lori L
LL
Stohl
Wanhong
W
Ding
Jason
J
Wong
Michael
M
Schierl
Xi K
XK
Zhou
Joel S
JS
Gordon
Eduardo
E
Perez
Maxwell B
MB
Stock
Richard D
RD
Granstein
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D016209:Interleukin-8; C079500:N-acetyl-S-geranylcysteine; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D000242:Cyclic AMP; C068268:N-acetyl-S-farnesylcysteine; D000111:Acetylcysteine