Culture of human monocytes with granulocyte-macrophage colony-stimulating factor results in enhancement of IFN-gamma receptors but suppression of IFN-gamma-induced expression of the gene IP-10.
The initiation and promulgation of chronic inflammation are controlled in part by the various pro-inflammatory and anti-inflammatory cytokines present at the site of injury. IFN-gamma and granulocyte-macrophage CSF (GM-CSF) are two cytokines that can contribute to the inflammatory state and possess both pro- and anti-inflammatory properties. However, the characterization of the interaction between GM-CSF-cultured monocytes and IFN-gamma is poorly documented. In this report we show that culture of human peripheral blood monocytes for up to 6 days in the presence of GM-CSF results in an eightfold increase in the level of IFN-gamma R expression, as determined by radioligand binding. The IFN-gamma R on these cells maintains a specificity typical of that observed in fresh monocytes. Only IFN-gamma, not IFN-alpha or -beta, blocks the binding of IFN-gamma to its receptor, and anti-IFN-gamma R antibodies block at least 80% of binding of IFN-gamma to these cultured cells. However, in spite of increased receptor expression, GM-CSF-cultured monocytes have a diminished response to IFN-gamma, as measured by the induction of the gene for IP-10 (a member of the platelet factor-4/IL-8 family). On the other hand, IFN-gamma-induced activation of the DNA-binding protein FcRF gamma is maintained in GM-CSF-cultured monocytes. Therefore, suppression of IFN-gamma-mediated IP-10 induction is not the result of a global abrogation of signal transduction across the IFN-gamma R but a more selective inhibition that appears to occur downstream of the receptor.
Finbloom
D S
DS
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD 20892.
Larner
A C
AC
Nakagawa
Y
Y
Hoover
D L
DL
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000187:drug effects; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D017471:Receptors, Interferon / Q000032:analysis / Q000187:drug effects*; D000096743:Interferon gamma Receptor
D000276:Adjuvants, Immunologic; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D008565:Membrane Proteins; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor