Human tribbles homologue 2 is expressed in unstable regions of carotid plaques and regulates macrophage IL-10 in vitro.
Mammalian orthologues of the Drosophila tribbles protein (Trb1, Trb2 and Trb3) are a recently described family of signalling molecules that regulate gene expression by modulation of protein kinase signalling pathways. In the present study, a screen for mRNA species specifically regulated in vulnerable regions of human atherosclerotic plaque demonstrated the up-regulation of both Trb1 and Trb2, the latter by more than 8-fold. In vitro experiments in primary human monocyte-derived macrophages showed that Trb2 expression was up-regulated by treatment with oxidized LDL (low-density lipoprotein), and that expression of recombinant Trb2 specifically reduced macrophage levels of IL-10 (interleukin-10) mRNA. Our results thus identify Trb2 as a highly regulated gene in vulnerable atherosclerotic lesions, and demonstrate inhibition of macrophage IL-10 biosynthesis as a potential pro-inflammatory consequence of high Trb2 expression, which may contribute to plaque instability.
Deng
Jingti
J
GlaxoSmithKline Clinical Unit, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge CB2 2GG, U.K.
James
Christian H
CH
Patel
Lisa
L
Smith
Alberto
A
Burnand
Kevin G
KG
Rahmoune
Hassan
H
Lamb
Jonathan R
JR
Davis
Bill
B
D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000601:surgery; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016894:Endarterectomy, Carotid; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018797:Cell Cycle Proteins; D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D012097:Repressor Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C493170:TRIB1 protein, human; C474831:TRIB3 protein, human; C099252:oxidized low density lipoprotein; C489044:TRIB2 protein, human