Role of toll-like receptors in realization of human chorionic gonadotropin effects on monocyte functional activity

Abstract

Human chorionic gonadotropin (hCG) is analyzed here as an endogenous ligand for type 4 Toll-like proteins (TLR4). It is demonstrated that hCG actively binds to TLR4 molecules on monocyte surfaces. Using flow cytometry it was revealed that in the presence of high hCG concentrations (100 and 1000 IU/mL) the level of CD14+TLR4+-positive cells was reliably lowered in the gate of monocytes on 1, 5, and 10 min of experiment. Inhibition assay was used to study the role of TLR4 molecules in realization of hCG effects on monocyte functional activity. Monoclonal antibodies against TLR4 and/or resveratrol that blocks TRIF/TRAF6 intracellular proteins involved in signal transduction to IRF3 and NF-κB, respectively were applied to block TLR4-dependent signal transduction. In addition, protein kinase A (PKA) engaged in signal transduction from LH-receptor was suppressed. It was revealed that the inhibitory effect of hCG on monocyte phagocytic activity was TLR4-dependent, whereas its effects on myeloperoxidase (MPOex) secretion and spontaneous oxidative monocyte activity were PKA-dependent. It was found that hormone effects on stimulated oxidative activity of monocytes and their production of interleukin (IL)-1 and IL-8 depended both on TLR4 availability and PKA activity. Thus, a novel mechanism of hormone-monocyte interactions has been revealed that is mediated by TLR4 molecules that serve as non-canonical hormone receptors in monocytes.