IL-4, IL-10 and IFN-gamma have distinct, but interacting, effects on differentiation-induced changes in TNF-alpha and TNF receptor release by cultured human monocytes.
Monocytes cultured in vitro differentiate to a macrophage-like phenotype and undergo functional changes, including reduced capacity for release of TNF-alpha and the soluble p55 receptor for TNF (sTNF-R55) but enhanced capacity for release of the soluble p75 receptor (sTNF-R75). The cytokines IL-4 and IL-10 act on monocytes to suppress the release of pro-inflammatory cytokines, including TNF-alpha, and to influence the release of sTNF-R. We therefore investigated the influence of differentiation over 15 days in vitro on the spontaneous and LPS- and IFN-gamma-induced release of TNF-alpha and sTNF-R from human monocytes and examined the actions of IL-4 and IL-10 on these. Unstimulated monocytes did not release TNF-alpha at any stage but released progressively larger amounts of sTNF-R75 with time. LPS-stimulated release of TNF-alpha declined substantially after the first day and was consistently suppressed by IL-10 and IL-4 but increased by IFN-gamma. Monocytes cultured with IL-10 released more sTNF-R75 at all times and expressed more mRNA for TNF-R75 at day 8. LPS stimulation consistently enhanced both spontaneous and IL-10-augmented release of sTNF-R75, whilst IFN-gamma co-stimulation consistently suppressed them. The influence of IL-4 on sTNF-R75 release, however, depended qualitatively on both the length of time in culture and on conditions of stimulation. The effects of LPS and IFN-gamma on TNF-alpha and sTNF-R75 release were progressively lost with increasing time in culture in the presence of IL-4. sTNF-R55 was not detectable after the first day of culture under any of these conditions. IL-4, IL-10 and IFN-gamma therefore have distinct, but interacting, effects on the balance between TNF-alpha and sTNF-R75 release by maturing monocytes. These interactions may be relevant to the pathogenesis or treatment of TNF-alpha-mediated diseases, where sTNF-R may act to neutralize or stabilise TNF, thereby modifying biological activity.
Joyce
D A
DA
Department of Pharmacology, University of Western Australia, Nedlands.
Steer
J H
JH
D000704:Analysis of Variance; D015152:Blotting, Northern; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma