Transactivation by the p65 subunit of NF-kappaB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1.
We have examined the involvement of components of the interleukin-1 (IL-1) signaling pathway in the transactivation of gene expression by the p65 subunit of NF-kappaB. Transient transfection of cells with plasmids encoding wild-type MyD88, IL-1 receptor-associated kinase 1 (IRAK-1), and TRAF-6 drove p65-mediated transactivation. In addition, dominant negative forms of ... MyD88, IRAK-1, and TRAF-6 inhibited the IL-1-induced response. In cells lacking MyD88 or IRAK-1, no effect of IL-1 was observed. Together, these results indicate that MyD88, IRAK-1, and TRAF-6 are important downstream regulators of IL-1-mediated p65 transactivation. We have previously shown that the low-molecular-weight G protein Rac1 is involved in this response. Constitutively active RacV12-mediated transactivation was not inhibited by dominant negative MyD88, while dominant negative RacN17 inhibited the MyD88-driven response, placing Rac1 downstream of MyD88 on this pathway. Dominant negative RacN17 inhibited wild-type IRAK-1- and TRAF-6-induced transactivation, and in turn, dominant negative IRAK-1 and TRAF-6 inhibited the RacV12-driven response, suggesting a mutual codependence of Rac1, IRAK-1, and TRAF-6 in regulating this pathway. Finally, Rac1 was found to associate with the receptor complex via interactions with both MyD88 and the IL-1 receptor accessory protein. A pathway emanating from MyD88 and involving IRAK-1, TRAF-6, and Rac1 is therefore involved in transactivation of gene expression by the p65 subunit of NF-kappaB in response to IL-1.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Antigens, Differentiation, Cell Line, Humans, Interleukin-1, Interleukin-1 Receptor Accessory Protein, Interleukin-1 Receptor-Associated Kinases, Mice, Myeloid Differentiation Factor 88, NF-kappa B, Protein Kinases, Proteins, Receptors, Immunologic, Receptors, Interleukin-1, Signal Transduction, TNF Receptor-Associated Factor 6, Transcription Factor RelA, Transcriptional Activation, Tumor Cells, Cultured, rac1 GTP-Binding Protein
Adaptor Proteins, Signal Transducing, Animals, Antigens, Differentiation, Cell Line, Humans, Interleukin-1, Interleukin-1 Receptor Accessory Protein, Interleukin-1 Receptor-Associated Kinases, Mice, Myeloid Differentiation Factor 88, NF-kappa B, Protein Kinases, Proteins, Receptors, Immunologic, Receptors, Interleukin-1, Signal Transduction, TNF Receptor-Associated Factor 6, Transcription Factor RelA, Transcriptional Activation, Tumor Cells, Cultured, rac1 GTP-Binding Protein
Mol. Cell. Biol.
Date: Jul. 01, 2001
PubMed ID: 11416133
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