title: Activating transcription factor 3 contributes to Toll-like receptor-mediated macrophage survival via repression of Bax and Bak.
abstract: Macrophages play an essential role in the innate immune response to infection and tissue injury. However, excessive macrophage activation may also significantly contribute to chronic inflammatory diseases. The Toll-like receptor (TLR) family are key regulators of innate immune responses in macrophages, and they are able to promote their survival and resistance against apoptosis. We, and others, have shown that the adaptive response gene, activating transcription factor 3 (ATF3), acts as a negative regulator of TLR signaling by repressing transcription of pro-inflammatory cytokines in primary mouse macrophages. Here, we describe a novel role for ATF3 as a component of TLR-mediated survival in macrophages. ATF3-deficient bone marrow macrophages show reduced survival in response to a range of TLR ligands and significantly higher apoptotic rates were observed in response to lipopolysaccharide, indicating that ATF3 is required to suppress apoptosis in macrophages. Furthermore, we show that ATF3 lies downstream of JNK signaling after TLR engagement, resulting in repression of pro-apoptotic Bak and Bax transcription.
authors.affiliation: Monash Institute of Medical Research, Monash University , Clayton, Victoria, Australia .
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Thompson
authors.forename: Dakang
authors.initials: D
authors.lastname: Xu
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
mesh_terms: D051700:Activating Transcription Factor 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D015536:Down-Regulation; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051193:Toll-Like Receptors / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D051193:Toll-Like Receptors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein