Prednisolone-Induced Changes in Gene-Expression Profiles in Healthy Volunteers

Abstract

Background: Prednisolone and other glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive drugs. However, prolonged use at a medium or high dose is hampered by side effects of which the metabolic side effects are most evident. Relatively little is known about their effect on gene-expression in vivo, the effect on cell subpopulations and the relation to the efficacy and side effects of GCs. Aim: To identify and compare prednisolone-induced gene signatures in CD4⁺ T lymphocytes and CD14⁺ monocytes derived from healthy volunteers and to link these signatures to underlying biological pathways involved in metabolic adverse effects. Materials & methods: Whole-genome expression profiling was performed on CD4⁺ T lymphocytes and CD14⁺ monocytes derived from healthy volunteers treated with prednisolone. Text-mining analyses was used to link genes to pathways involved in metabolic adverse events. Results: Induction of gene-expression was much stronger in CD4⁺ T lymphocytes than in CD14⁺ monocytes with respect to fold changes, but the number of truly cell-specific genes where a strong prednisolone effect in one cell type was accompanied by a total lack of prednisolone effect in the other cell type, was relatively low. Subsequently, a large set of genes was identified with a strong link to metabolic processes, for some of which the association with GCs is novel. Conclusion: The identified gene signatures provide new starting points for further study into GC-induced transcriptional regulation in vivo and the mechanisms underlying GC-mediated metabolic side effects.

Original submitted 5 January 2011; Revision submitted 24 February 2011

KEYWORDS::

• gene signature
• glucocorticoids
• metabolic side effects
• prednisolone
• whole-genome expression profiling

Financial & competing interests disclosure

Clinical trial number: NCT00971724. This work was performed within the framework of Dutch Top Institute Pharma, project ‘Glucocorticoid-induced insulin resistance‘ (project nr. T1-106-1). Ulla Nässander, Marie-José C van Lierop, Susanne Bauerschmidt, Wim HA Dokter and Wynand Alkema are all employees of Merck, Sharp and Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Clinical trial number: NCT00971724. This work was performed within the framework of Dutch Top Institute Pharma, project ‘Glucocorticoid-induced insulin resistance‘ (project nr. T1-106-1). Ulla Nässander, Marie-José C van Lierop, Susanne Bauerschmidt, Wim HA Dokter and Wynand Alkema are all employees of Merck, Sharp and Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.