Involvement of TBK1 and IKKϵ in lipopolysaccharide‐induced activation of the interferon response in primary human macrophages
Open Access
- 1 February 2007
- journal article
- leukocyte signaling
- Published by Wiley in European Journal of Immunology
- Vol. 37 (2), 528-539
- https://doi.org/10.1002/eji.200636090
Abstract
Interferon (IFN) is an important effector of the innate immune response, induced by different viral or bacterial components through Toll-like receptor-dependent and -independent mechanisms. In human macrophages and macrophage-activated killer cells, we demonstrate that (i) the type I IFN response to lipopolysaccharide (LPS) is weak compared to the host response to virus infection; (ii) there is a temporal difference in the induction of tank-binding kinase-1 (TBK1) and IkappaB kinase (IKK)-related kinase epsilon (IKKϵ) kinase activities in response to LPS, with TBK1 activated early and IKKϵ induced in the late phase of IFN induction; and (iii) interferon regulatory factor (IRF)-7 is induced following LPS treatment, but there is no evidence that IRF-7 becomes activated by phosphorylation in vivo. Specifically, TBK1 kinase activity is rapidly increased after LPS stimulation (15 min) whereas IKKϵ activation occurs at 8 h. RNA interference-mediated inhibition of TBK1 and IKKϵ expression in macrophages interfere with IFNB and IRF7 gene expression following LPS activation. Macrophage priming with rIFN-α increased IRF-7 expression, led to a sharp up-regulation of the IFNB gene and to a rapid induction of IFNA2 upon LPS stimulation. These data support a differential role of TBK1 and IKKϵ in the downstream response mediated by IRF-3 and IRF-7 to LPS in primary human macrophages.Keywords
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