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The dual functions of IL-1 receptor-associated kinase 2 in TLR9-mediated IFN and proinflammatory cytokine production
Journal article   Peer reviewed

The dual functions of IL-1 receptor-associated kinase 2 in TLR9-mediated IFN and proinflammatory cytokine production

Youzhong Wan, Tae Whan Kim, Minjia Yu, Hao Zhou, Michifumi Yamashita, Zizhen Kang, Weiguo Yin, Jian-An Wang, James Thomas, Ganes C Sen, …
The Journal of immunology (1950), Vol.186(5), pp.3006-3014
03/01/2011
DOI: 10.4049/jimmunol.1003217
PMCID: PMC3163905
PMID: 21270393

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Abstract

Bone marrow-derived plasmacytoid dendritic cells (pDCs) from IL-1R-associated kinase (IRAK)2-deficient mice produced more IFNs than did wild-type pDCs upon stimulation with the TLR9 ligand CpG. Furthermore, in CpG-stimulated IRAK2-deficient pDCs there was increased nuclear translocation of IFN regulatory factor 7, the key transcription factor for IFN gene transcription in these cells. In IRAK2-deficient macrophages, enhanced NF-κB activation and increased expression of CpG-induced genes were detected within 2 h after treatment. However, at later times, NF-κB activation was decreased and, in contrast to the results with IFN, there was less secretion of other proinflammatory cytokines (such as TNF-α) and chemokines in CpG-stimulated IRAK2-deficient pDCs and macrophages. Therefore, although IRAK2 is a negative regulator of TLR9-mediated IFN production through its modulation of the transcriptional activity of IFN regulatory factor 7, it is also a positive regulator of TLR9-mediated proinflammatory cytokine and chemokine production at some level subsequent to transcription.
 Animals Cells, Cultured CpG Islands - immunology Cytokines - antagonists & inhibitors Cytokines - biosynthesis Cytokines - physiology Dendritic Cells - immunology Dendritic Cells - metabolism Down-Regulation - immunology Herpesviridae Infections - enzymology Herpesviridae Infections - immunology Herpesviridae Infections - pathology Inflammation Mediators - antagonists & inhibitors Inflammation Mediators - metabolism Inflammation Mediators - physiology Interferon Regulatory Factor-7 - antagonists & inhibitors Interferon Regulatory Factor-7 - physiology Interferon Type I - antagonists & inhibitors Interferon Type I - biosynthesis Interferon-alpha Interferon-beta - antagonists & inhibitors Interferon-beta - biosynthesis Interleukin-1 Receptor-Associated Kinases - deficiency Interleukin-1 Receptor-Associated Kinases - physiology Ligands Mice Mice, Knockout Recombinant Proteins Rhadinovirus - immunology Toll-Like Receptor 9 - metabolism Toll-Like Receptor 9 - physiology Tumor Virus Infections - enzymology Tumor Virus Infections - immunology Tumor Virus Infections - pathology

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