Differential role for c-Rel and C/EBPbeta/delta in TLR-mediated induction of proinflammatory cytokines.
TLR stimulation triggers a signaling pathway via MyD88 and IL-1R-associated kinase 4 that is essential for proinflammatory cytokine induction. Although NF-kappaB has been shown to be one of the key transcriptional regulators of these cytokines, evidence suggests that other factors may also be important. In this study, we showed that MyD88-deficient macrophages have defective c-Rel activation, which has been linked to IL-12p40 induction, but not IL-6 or TNF-alpha. We also investigated other transcription factors and showed that C/EBPbeta and C/EBPdelta expression was limited in MyD88- or IL-1R-associated kinase 4-deficient macrophages treated with LPS. Importantly, the absence of both C/EBPbeta and C/EBPdelta resulted in the impaired induction of proinflammatory cytokines stimulated by several TLR ligands. Our results identify c-Rel and C/EBPbeta/delta as important transcription factors in a MyD88-dependent pathway that regulate the induction of proinflammatory cytokines.
Lu
Yong-Chen
YC
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Ontario, Canada.
Kim
Ira
I
Lye
Elizabeth
E
Shen
Fang
F
Suzuki
Nobutaka
N
Suzuki
Shinobu
S
Gerondakis
Steve
S
Akira
Shizuo
S
Gaffen
Sarah L
SL
Yeh
Wen-Chen
WC
Ohashi
Pamela S
PS
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D018836:Inflammation Mediators; D053592:Interleukin-1 Receptor-Associated Kinases; D008264:Macrophages; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D051193:Toll-Like Receptors / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology
D022782:CCAAT-Enhancer-Binding Protein-beta; C497253:Cebpd protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D020569:Proto-Oncogene Proteins c-rel; D051193:Toll-Like Receptors; D051743:CCAAT-Enhancer-Binding Protein-delta; D053592:Interleukin-1 Receptor-Associated Kinases