Glucocorticoids inhibit IL-4 and mitogen-induced IL-4Rα chain expression by different posttranscriptional mechanisms

Background: A high level of expression of IL-4R alpha chain on the surface of lymphocytes has been described in certain allergic and inflammatory autoimmune diseases. Progression of these diseases are usually controlled by steroid treatment. One mechanism by which these drugs exert their antiinflammatory and immunosuppressive effects is by widely repressing or enhancing the production of cytokines and their receptors. Objectives: The effect of glucocorticoids on IL-4R alpha chain expression has not been previously studied, and this is the aim of the present report. For this purpose, human lymphocytes were induced to express IL-4R alpha chain by means of protein kinase C (PKC) activation with phorbol myristate acetate (PMA) or by triggering the Janus kinase-Stat pathway with IL-4 in the presence or absence of pharmacologic doses of dexamethasone. Methods: IL-4R alpha cell surface expression was studied by flow cytofluorometry. The levels and stability of mRNA were assessed by Northern blot analysis. The effect of dexamethasone on the IL-4R alpha rate of transcription was determined by nuclear run-on experiments. Results: Dexamethasone significantly downregulated PMA-induced IL-4R alpha mRNA and protein levels in total peripheral blood mononuclear cells and in isolated T cells. The mechanism involved a posttranscriptional regulation of IL-4R alpha expression because dexamethasone decreased the PMA-induced IL-4R alpha mRNA half-life. However, we found that PMA did not influence the transcription rate of IL-4R alpha gene, irrespective of the presence or absence of dexamethasone. This immunosuppressor also diminished the IL-4induced IL-4R alpha expression on the surface of isolated T and B lymphocytes but, interestingly, without modifying mRNA levels that indicates that dexamethasone downregulated IL-4-dependent IL-4R alpha expression by acting at a translational or posttranslational level. In fact, we observed that the drug did not affect IL-4-induced IL-4R alpha gene transcription rate nor did it shorten mRNA half-life. The effect of dexamethasone on the IL-4R alpha was steroid specific because it was totally reversed by the glucocorticoid receptor antagonist RU486. Conclusion: Our results support that dexamethasone may influence the course of allergic and inflammatory diseases by downregulating the expression of IL-4R alpha.