Effect of tacrolimus on the expression of macrophage scavenger and nuclear hormone receptors in THP-1-derived human macrophages.
BACKGROUND
Data indicate that tacrolimus and cyclosporine A (CsA) differentially affect the risk of atherosclerosis. The results of our recent in vitro studies of clinically relevant CsA concentrations demonstrated the modulation of macrophage scavenger receptors (MSRs) involved in atherogenesis. This work evaluated the effects of clinically relevant tacrolimus concentrations on the expression of the MSR genes CD36 and CD68, SR-A and SR-BII, lectin-like oxidized low-density lipoprotein receptor-1, the nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR)gamma and liver-X-receptor-alpha, and the cholesterol efflux pump ABCA1 in the in vitro human THP-1 macrophage model.


METHODS
The cells were cultured and differentiated into macrophages. Macrophages were treated with the tacrolimus to assess gene expression in a time-dependent (1, 2, 4, 8, and 24 hr) and dose-dependent (concentrations [micrograms/liter] corresponding to the trough [15], peak [30], and 4 x peak [120]) manner using reverse-transcriptase polymerase chain reactions. The gene expression levels of interest were normalized to GAPDH expression in each sample to provide semiquantitative reverse-transcriptase polymerase chain reaction results. Additional immunoblotting studies demonstrated protein expression of CD36, PPARgamma, and ABCA1. RESULTS.: The gene expression of CD36, SR-BII, and lectin-like oxidized low-density lipoprotein receptor-1 were down-regulated, and ABCA1 was up-regulated. CD68, SR-AI, liver-X-receptor-alpha, and PPARgamma were regulated in a dose-dependent manner. Protein expression of CD36 was down-regulated, and PPARgamma and ABCA1 were relatively unchanged.


CONCLUSIONS
Tacrolimus seems to regulate MSRs, nuclear hormone receptors, and ABCA1 in THP-1 macrophages. These results differ from previous findings with CsA and may provide insight into the mechanisms of posttransplant atherosclerosis.
Jin
Song
S
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Mathis
A Scott
AS
Gioia
Kevin
K
Minko
Tamara
T
Friedman
Gary S
GS
Rosenblatt
Joseph
J
Peng
Felice
F
Serur
David S
DS
Knipp
Gregory T
GT
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics; D002460:Cell Line; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology*; D000097382:CD68 Molecule
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018955:CD36 Antigens; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D016559:Tacrolimus; C577836:ABCA1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule