title: Differential gene expression of interleukin-1 receptor associated kinase-1 and interleukin-1 receptor associated kinase-M in peripheral blood mononuclear cells of young and aged rats following preconditioning with endotoxin.
abstract: The IL-1 receptor-associated kinase 1 (IRAK-1) and IRAK-M are key signaling molecules in cellular responses to endotoxin initiated through the Toll-like receptors (TLRs). The aim of this study was to evaluate the effect of age on the modulation of TLRs and IRAK-1 and IRAK-M in peripheral blood mononuclear cells (PBMCs) exposed in vitro to endotoxin under conditions that could induce endotoxin tolerance. Peripheral blood mononuclear cells obtained from young (4- to 6-month-old) and aged (24- to 26-month-old) Brown Norway rats were treated with high-dose LPS, with or without priming with low-dose LPS. In comparison with younger rats, the intensity of TLR-4 expression was persistently high in monocytes from aged rats after stimulation with LPS and was not decreased by priming with low-dose LPS (P < 0.05). Messenger RNA (mRNA) for TLR-4 in PBMCs from aged rats did not show any decrease after priming with low-dose LPS as seen in PBMCs from young rats at 24 h (P = 0.01) after restimulation. In PBMCs from young rats, but not aged rats, preconditioning with low-dose LPS and subsequent stimulation with high-dose LPS resulted in markedly decreased IRAK-1 protein (P = 0.02) and decreased mRNA for IRAK-1 (P < 0.05). In contrast, PBMCs from aged rats treated in this manner continued to express measurable levels of IRAK-1 protein. Preconditioning with low-dose LPS caused an increase in both IRAK-M protein and mRNA (P = 0.05) after stimulation with high-dose LPS only in cells from young rats. These phenotypic characteristics of PBMCs from aged rats can interfere with their ability to develop tolerance to endotoxin.
authors.affiliation: Department of Surgery, Duke University, USA.
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Li
authors.forename: E Annette
authors.initials: EA
authors.lastname: Howell
authors.forename: Anand S
authors.initials: AS
authors.lastname: Lagoo
authors.forename: Maragatha
authors.initials: M
authors.lastname: Kuchibhatla
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Cohen
authors.forename: Sandhya A
authors.initials: SA
authors.lastname: Lagoo
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D051381:Rats; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis
chemical_list: D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C433788:lipopolysaccharide, E. coli O26-B6; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases