2024-03-28T19:24:30Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/302702022-11-17T02:08:08Zhdl_2115_20042hdl_2115_136Apoptosis signal-regulating kinase 1-mediated sustained p38 mitogen-activated protein kinase activation regulates mycoplasmal lipoprotein- and staphylococcal peptidoglycan-triggered Toll-like receptor 2 signalling pathwaysInto, TakeshiShibata, Ken-ichiroTLR2ASK1p38 MAPKAP-1NF-κBcaspase465Toll-like receptor (TLR) 2 functions as a sensor for detecting various microbial components conserved in bacteria or fungi in innate immunity. TLR2 induces several signalling pathways linking to activation of the transcriptional factors NF-κB and AP-1 as well as induction of cell death. In human embryonic kidney 293 cells expressed human TLR2, mycoplasmal lipoproteins (MLP) or staphylococcal peptidoglycans (PGN) induced sustained phosphorylation of p38 mitogen-activated protein kinase (MAPK), accompanied by generation of reactive oxygen species. This observation encouraged us to examine roles of apoptosis signal-regulating kinase 1 (ASK1) in TLR2 signalling, because ASK1 is an upstream activator of p38 MAPK during exposure to oxidative stress and other stressful stimuli. A kinase-inactive mutant of ASK1 greatly impaired the sustained phosphorylation of p38 MAPK induced by MLP or PGN. This mutant also attenuated MLP- or PGN-induced transcriptional activities of NF-κB and AP-1 via inhibition of p38 MAPK activation. MLP- or PGN-induced cell death reactions, including DNA fragmentation and caspase-3/7 activation, were also downregulated by the ASK1 mutant via p38 MAPK inhibition. Furthermore, TLR2 signalling had a potential to phosphorylate and dephosphorylate ASK1 at Ser83 residue. Thus, MLP and PGN have capabilities to induce ASK1-dependent signalling pathways which regulate p38 MAPK activation through TLR2, leading to activation of NF-κB and AP-1 as well as induction of cell death.Blackwell PublishingJournal Articleapplication/pdfhttp://hdl.handle.net/2115/30270https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/30270/1/CM7-9.pdf1462-58141462-5822Cellular Microbiology79130513172005-09enginfo:pmid/16098218info:doi/10.1111/j.1462-5822.2005.00558.xThe definitive version is available at www.blackwell-synergy.comauthor