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Apoptosis signal‐regulating kinase 1‐mediated sustained p38 mitogen‐activated protein kinase activation regulates mycoplasmal lipoprotein‐ and staphylococcal peptidoglycan‐triggered Toll‐like receptor 2 signalling pathways

Toll‐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.