Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide.
In human monocytes and macrophages, interferon-gamma (IFNgamma) 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. IFNgamma counteracted the LPS-induced downregulation of TLR4. IFNgamma-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-kB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor alpha [TNFalpha] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNgamma of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.
Bosisio
Daniela
D
Department of Immunology and Cell Biology, Mario Negri Institute, Milano, Italy.
Polentarutti
Nadia
N
Sironi
Marina
M
Bernasconi
Sergio
S
Miyake
Kensuke
K
Webb
Ginette R
GR
Martin
Michael U
MU
Mantovani
Alberto
A
Muzio
Marta
M
D000954:Antigens, Surface / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D029721:Drosophila Proteins; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D017472:Receptors, Interleukin-1; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000187:drug effects
D000954:Antigens, Surface; D002352:Carrier Proteins; D029721:Drosophila Proteins; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases