Selective glucocorticoid-mediated apoptosis of in GM-CSF-treated monocytes – a novel mechanism for preventing excessive inflammation


The profound effects of glucocorticoids in immunosuppressive and anti-inflammatory therapy are due to their potent modulation of diverse physiological processes. These effects are mediated by their ability to inhibit the synthesis of proinflammatory mediators by monocytes/macrophages and induce changes in the process of phagocytosis, cell survival, and proliferation. In spite of the benefits associated with the use of exogenous glucocorticoids, their long-term use causes negative side-effects in patients. This has necessitated the investigation of the mode of action of glucocorticoids on immune cells, particularly the regulation of survival/death signaling pathways in monocytes. Thus, this study proposed a novel mechanism of action, in which glucocorticoids participate in the selective regulation of inflammatory processes.

Dr. Adrian Achuthan and colleagues at the University of Melbourne in Australia demonstrated that the addition of glucocorticoids resulted in the inhibition of ERK/12 phosphorylation, which triggers the apoptosis of monocytes treated with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF). The work is published in the peer-reviewed journal, Cell Death and Disease.

The research team observed that the monocytes co-treated with GM-CSF and dexamethasone (Dex) showed increased numbers of cell death compared to monocytes treated with only GM-CSF. The pretreatment of GM-CSF-treated monocytes and GM-CSF and Dex-treated monocytes with mifepristone (a glucocorticoid receptor antagonist) resulted in the abrogation of glucocorticoid-induced apoptosis.

Their study also revealed that the presence of GM-CSF or Macrophage Colony Stimulating Factor, induced the activation of ERK1 and basal ERK2 phosphorylation while the co-treatment of dexamethasone caused a decrease in the activity of GM-CSF induced ERK1, basal ERK2 phosphorylation and reduced levels of RSK activity. The pre-treatment of co-treated monocytes with mifepristone restored the induction of ERK1 and ERK2 basal phosphorylation and resulted in an increase in RSK activities.

Furthermore, the authors observed that the induction of ERK1 activity and ERK2 basal phosphorylation did not result in the abrogation of pro-apoptotic Bad protein phosphorylation in monocytes treated with GM-CSF alone, M-CSF alone and GM-CSF and dexamethasone. However, the inhibition of ERK1 activity and ERK2 basal phosphorylation resulted in the abrogation of Bad phosphorylation in monocytes co-treated with GM-CSF and Dex. There was a strong correlation between the increase in bad phosphorylation and a decrease in apoptotic monocytes.

Adrian Achuthan and colleagues study successfully identified a novel molecular mechanism of glucocorticoids-induced apoptosis of proinflammatory monocytes via the inhibition of ERK activity. The detailed findings explicate the clinical significance of selective glucocorticoids-mediated apoptosis of proinflammatory monocytes/macrophages in the treatment of autoimmune and inflammatory diseases.

Selective glucocorticoid-mediated apoptosis of in GM-CSF-treated monocytes – a novel mechanism for preventing excessive inflammation - Medicine Innovates
Selective glucocorticoid-mediated apoptosis of in GM-CSF-treated monocytes – a novel mechanism for preventing excessive inflammation

About the author

Dr Adrian Achuthan is a researcher at the University of Melbourne focused on developing new therapies to manage inflammation and pain in chronic inflammatory diseases. He graduated with a Biomedical science degree (Honours) from University of Melbourne, where he also obtained his doctorate in 2008. He pursued further training at the Institute of Molecular and Cell Biology in Singapore, supported by an Australian Government Endeavour Research Fellowship and completed a stint at the Burnette Institute, Melbourne. He subsequently returned to the University of Melbourne to pursue his passion in exploring the functional roles of monocytes/ macrophages/dendritic cells in the progression of arthritic pain and disease. He is successful is securing several grants from the Government, Industry and philanthropic organizations for translational research projects, which have led to the creation of two patents and multiple publications in high impact journals.


Achuthan, A., Aslam, A.S.M., Nguyen, Q., Lam, P. Y., Fleetwood, A.J., Frye, A.T., Louis, C., Lee, M.C., Smith, J.E., Cook, A.D., Olshansky, M., Turner, S.J. and Hamilton, J.A . Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity, Cell Death & Disease, volume 9, Article number: 267 (2018)

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