Glucocorticoids (GCs) mediate their action by down-regulating the transcription of multiple inflammatory gene products. In doing so, they can be used to control asthma, to limit hypersensitivity to allergens, and to prevent graft rejection. Although these clinical uses are benefits of this action of GC, their use also suppress a patient's immune response to infectious pathogens. Objectives: Previous data show that the androgen steroid hormone, androstenediol (AED), reduced the anti-inflammatory actions of GC; thus, the current study was designed to determine how AED mediated this anti-glucocorticoid function. It was recently posited that GCs can negatively influence inflammation by interfering with mitogen-activated protein kinase (MAPK) signaling pathways and can do so by inducing the transcription of the phosphatase MKP-1 (MAP kinase phosphatase-1). MKP-1 inactivates three MAPK pathways (ERK, JNK, and p38) via dephosphorylation of threonine and tyrosine residues within the activation motif of all three kinases. Methods: In the current study, a model was established in which we could determine the effects of GC on MKP-1 gene expression. Using murine macrophages (RAW 264.7 cells), we measured the influence of dexamethasone on MKP-1 gene expression using real-time PCR. Results: The data showed that 10-7M DEX induced a 7.5 fold increase in MKP-1 RNA 30 minutes after stimulation. In contrast, AED (10-7M) caused a 1.6 fold decrease of MKP-1 expression relative to controls. However, co-culture with AED and DEX indicated a further enhancement of MKP-1 RNA as compared DEX alone. Conclusions: Therefore, because AED failed to block GC-induced MKP-1 gene expression, the data suggest that indicate that the anti-inflammatory actions of glucocorticoids may be independent of GC-driven MKP-1 gene expression. However, given the ability of AED to independently suppress MKP-1, we propose further investigation into the effects of AED pre-treatment on GC-induced gene expression. Supported by T32DE014320-05

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