Toll-like receptor cross-hyporesponsiveness is functional in interleukin-1-receptor-associated kinase-1 (IRAK-1)-deficient macrophages: differential role played by IRAK-1 in regulation of tumour necrosis factor and interleukin-10 production.
Signalling downstream Toll-like receptors (TLR) is regulated at several levels in order to activate the immune response and prevent excessive inflammation. Altered intracellular signalling may be one reason that repeated stimulation of various TLRs results in hyporesponsiveness and cross-tolerance. We report that TLR cross-tolerance is inducible in the absence of interleukin-1 receptor-associated kinase-1 (IRAK-1) in peritoneal macrophages. Similar to wild-type macrophages, IRAK-1-deficient macrophages respond with decreased tumour necrosis factor (TNF) production to a secondary TLR stimulation, but in opposite to IRAK-1(+/+), IRAK-1(-/-) macrophages display increased interleukin (IL)-10 production at TLR restimulation. IRAK-1-deficient peritoneal macrophages have a defective TNF and IL-10 production in response to lipoteichoic acid stimulation as well as a defective IL-10-but a normal TNF production in response to high concentration of lipopolysaccharide. Our results demonstrate that IRAK-1 is not necessary for induction of TLR cross-tolerance as judged by TNF production.
Berglund
M
M
Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. martin.berglund@immuno.gu.se
Thomas
J A
JA
Hörnquist
E H
EH
Hultgren
O H
OH
D000818:Animals; D002478:Cells, Cultured; D007108:Immune Tolerance; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D016328:NF-kappa B; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C009900:lipoteichoic acid; D053592:Interleukin-1 Receptor-Associated Kinases