Glucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is 
complex and still debatable. One likely cellular target of GCs are 
monocytes/macrophages. The role of GCs in monocyte survival is also debated. 
Although both granulocyte macrophage-colony stimulating factor (GM-CSF) and 
macrophage-CSF (M-CSF) are important regulators of macrophage lineage functions 
including their survival, the former is often associated with proinflammatory 
functions while the latter is important in lineage homeostasis. We report here 
that the GC, dexamethasone, induces apoptosis in GM-CSF-treated human monocytes 
while having no impact on M-CSF-induced monocyte survival. To understand how 
GCs, GM-CSF, and M-CSF are regulating monocyte survival and other functions 
during inflammation, we firstly examined the transcriptomic changes elicited by 
these three agents in human monocytes, either acting alone or in combination. 
Transcriptomic and Ingenuity pathway analyses found that dexamethasone 
differentially modulated dendritic cell maturation and TREM1 signaling pathways 
in GM-CSF-treated and M-CSF-treated monocytes, two pathways known to be 
regulated by ERK1/2 activity. These analyses led us to provide evidence that the 
GC inhibits ERK1/2 activity selectively in GM-CSF-treated monocytes to induce 
apoptosis. It is proposed that this inhibition of ERK1/2 activity leads to 
inactivation of p90 ribosomal-S6 kinase and Bad dephosphorylation leading in 
turn to enhanced caspase-3 activity and subsequent apoptosis. Furthermore, 
pharmacological inhibition of GC receptor activity restored the ERK1/2 signaling 
and prevented the GC-induced apoptosis in GM-CSF-treated monocytes. Increased 
tissue macrophage numbers, possibly from enhanced survival due to mediators such 
as GM-CSF, can correlate with inflammatory disease severity; also reduction in 
these numbers can correlate with the therapeutic benefit of a number of agents, 
including GCs. We propose that the ERK1/2 signaling pathway promotes survival of 
GM-CSF-treated proinflammatory monocytes, which can be selectively targeted by 
GCs as a novel mechanism to reduce local monocyte/macrophage numbers and hence 
inflammation.