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

Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
Scandinavian Journal of Immunology (Impact Factor: 1.74). 06/2008; 67(5):473-9. DOI: 10.1111/j.1365-3083.2008.02096.x
Source: PubMed


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.

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Available from: Elisabeth Hultgren Hörnquist, Sep 25, 2014
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    • "Once phosphorylated, IRAK-1 activates IKKβ and JNK that ultimately leads to activation of the NF-κBinduced secretion of pro-inflammatory cytokines such as TNF-α (Skaug et al. 2009). In support of our results, Berglund et al. (2008) reported that IRAK-1-deficient peritoneal macrophages in mice have a defective TNF-α production in response LPS stimulation. In both rat adipocytes and bovine aortic endothelial cells, IRAK1 gene expression was upregulated after incubation with TNF-α, and the expression of IRAK1 lead to an increased expression of TNF (Kim et al. 2005). "
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