LPS-induced Toll-like receptor 4 signalling triggers cross-talk of apoptosis signal-regulating kinase 1 (ASK1) and HIF-1alpha protein

Toll-like receptor 4 (TLR4) is required for recognition of lipopolysaccharide (LPS) of Gram-negative bacteria and induction of the innate immune response to them. Nevertheless, the involvement of some crucial pathways in TLR4 signalling is poorly understood. Here, we report that LPS-induced TLR4 signalling triggers cross talk of HIF-1alpha and ASK1 in THP-1 human myeloid monocytic leukaemia cells. Both pathways are activated via redox-dependent mechanism associated with tyrosine kinase/phospholipase C-1gamma-mediated activation of protein kinase C alpha/beta, which are known to activate NADPH oxidase and the production of reactive oxygen species that activate both HIF-1alpha and ASK1. ASK1 contributes to the stabilisation of HIF-1alpha, most likely via activation of p38 MAP kinase.