Glucocorticoids inhibit activation-dependent expression of costimulatory molecule B7-1 in human monocytes

Abstract

Background: Glucocorticoids act as immunosuppressive drugs mainly via their effects on antigen-presenting cells. They are known to influence production of cytokines as well as expression of cell surface molecules. B7 molecules belong to the most important costimulatory signals for T-cell activation during transplant rejection. They are expressed on antigen-presenting cells and up-regulated during the immune response. We studied the influence of glucocorticoids on the regulation of these accessory signals.

Methods: Human monocytes were purified from peripheral blood of healthy volunteers by centrifugal counterflow elutriation. Activation-dependent transcription and expression of B7-1 (CD80) and B7-2 (CD86) were detected by reverse transcription-polymerase chain reaction and flow cytometry in the absence or presence of glucocorticoids.

Results: The expression pattern of B7-1 and B7-2 on monocytes depends on the type of stimulation. Activation by interferon-gamma induces both B7-1 and B7-2, whereas cAMP exclusively up-regulates B7-2. Glucocorticoids selectively inhibit the expression of B7-1 while leaving B7-2 unaffected. The effect occurs at concentrations that are reached during therapeutical application of the substances in humans. It is mediated via the cytoplasmic glucocorticoid receptor, as it can be abrogated by the glucocorticoid receptor antagonist RU38486. Inhibition of B7-1 occurs at the transcriptional level. Up-regulation of the molecule can similarly be inhibited by hydrocortisone, prednisolone, and dexamethasone at equipotent doses.

Conclusions: Inhibition of the up-regulation of B7-1 by glucocorticoids is a previously unknown mechanism of action of these substances and may relevantly contribute to their effects as immunosuppressive drugs.