IL-10 inhibits granulocyte-macrophage colony-stimulating factor-dependent human monocyte survival at the early stage of the culture and inhibits the generation of macrophages.
We previously demonstrated that IL-10 alone does not stimulate growth and differentiation of human monocytes, but enhances those of monocytes stimulated with M-CSF. We studied here the effect of IL-10 on human monocytes stimulated with GM-CSF. Monocytes stimulated with GM-CSF alone survived and developed into macrophages. Monocytes cultured with GM-CSF plus IL-10, however, died through apoptosis. IL-10 decreased expression of bcl-2, bcl-x(L), and mcl-1- but not bax mRNA in monocytes stimulated with GM-CSF. IL-10 did not change the expression of mRNA of both GM-CSFR alpha-chain and beta-chain, but inhibited tyrosine phosphorylation of STAT5 and extracellular signal-regulated kinases 1 and 2 in the monocytes. The inhibitory effect of IL-10 was restricted to treatment 48 h after stimulation with GM-CSF. Addition of IL-10 after that time induced neither apoptosis nor a decrease in expression of bcl-2, bcl-x(L), and mcl-1 mRNA. IL-10, however, inhibited LPS-induced TNF-alpha production even in these cells, indicating that the cells still possessed responsiveness to IL-10. Monocytes pretreated for >48 h with GM-CSF became resistant to GM-CSF withdrawal, and the cells could survive without GM-CSF. These results indicate that IL-10 selectively inhibits GM-CSF-dependent monocyte survival by inhibiting the signaling events induced by GM-CSF, but the timing of addition of IL-10 is critical, and IL-10 had to be added within 48 h after stimulation with GM-CSF to achieve the inhibitory effect. These results taken together with our previous results indicate that IL-10 plays a pivotal role in monocyte survival and development into macrophages in concert with M-CSF and GM-CSF.
Hashimoto
S I
SI
Department of Immunology, National Institutes of Health, Tokyo, Japan.
Komuro
I
I
Yamada
M
M
Akagawa
K S
KS
D017209:Apoptosis; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004336:Drug Antagonism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D007700:Kinetics; D008264:Macrophages / Q000276:immunology*; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases