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

Abstract

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-xL, 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 α-chain and β-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-xL, and mcl-1 mRNA. IL-10, however, inhibited LPS-induced TNF-α 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.

Spinal Fluid Abnormalities in Patients with Chronic Fatigue Syndrome

“…Although speculative, it is possible that the elevated levels of IL-10 found here are responsible for downregulation of GM-CSF in these patients. Supporting this hypothesis is a report showing that IL-10 inhibits GM-CSF-dependent monocyte survival and macrophage generation (9). The role of IL-8 is less clear but may be contributory.…”

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“…As for the THP-1 macrophages, these cells are PMAdifferentiated macrophages, and it is possible that PMA preactivation could contribute to the similarities between THP-1 macrophages and macrophages from ACS patients. Such an association between the degree of preactivation and the response to IL-10 stimulation has also been suggested by others (31).…”

Prostaglandin D2 Causes Preferential Induction of Proinflammatory Th2 Cytokine Production through an Action on Chemoattractant Receptor-Like Molecule Expressed on Th2 Cells

“…However, IL-10 has been defined previously as a cytokine synthesis inhibiting factor and represents one of the important immune-regulating cytokines (30). It is capable of inhibiting the synthesis of several cytokines from different cells and the function of several types of immune cells (31)(32)(33). In IL-10 gene-deficient mice, an overproduction of inflammatory cytokines and development of chronic inflammatory disease have been observed (34,35).…”