Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-γ: A molecular basis for priming and synergism with bacterial lipopolysaccharide

In human monocytes and macrophages, interferon-γ (IFNγ) augmented mRNA and surface expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Expression of the accessory component MD-2 and of the adapter protein MyD88 was also increased. LPS increased TLR4 mRNA levels, but concomitantly decreased its surface expression. IFNγ counteracted the LPS-induced downregulation of TLR4. IFNγ-primed monocytes showed increased responsiveness to LPS in terms of phosphorylation of the interleukin-1 receptor-associated kinase (IRAK; immediately downstream of the MyD88 adapter protein), NF-κB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor α [TNFα] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNγ of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.