Glucocorticoids inhibit IL-4 and mitogen-induced IL-4R alpha chain expression by different posttranscriptional mechanisms.
BACKGROUND
A high level of expression of IL-4Ralpha 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.


OBJECTIVE
The effect of glucocorticoids on IL-4Ralpha 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-4Ralpha 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-4Ralpha 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-4Ralpha rate of transcription was determined by nuclear run-on experiments.


RESULTS
Dexamethasone significantly downregulated PMA-induced IL-4Ralpha mRNA and protein levels in total peripheral blood mononuclear cells and in isolated T cells. The mechanism involved a posttranscriptional regulation of IL-4Ralpha expression because dexamethasone decreased the PMA-induced IL-4Ralpha mRNA half-life. However, we found that PMA did not influence the transcription rate of IL-4Ralpha gene, irrespective of the presence or absence of dexamethasone. This immunosuppressor also diminished the IL-4-induced IL-4Ralpha 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-4Ralpha expression by acting at a translational or posttranslational level. In fact, we observed that the drug did not affect IL-4-induced IL-4Ralpha gene transcription rate nor did it shorten mRNA half-life. The effect of dexamethasone on the IL-4Ralpha was steroid specific because it was totally reversed by the glucocorticoid receptor antagonist RU486.


CONCLUSIONS
Our results support that dexamethasone may influence the course of allergic and inflammatory diseases by downregulating the expression of IL-4Ralpha.
Mozo
L
L
Department of Immunology, Hospital Central de Asturias, Centro Universitario, Oviedo.
Gayo
A
A
Suárez
A
A
Rivas
D
D
Zamorano
J
J
Gutiérrez
C
C
D002478:Cells, Cultured; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008934:Mitogens / Q000494:pharmacology*; D014066:Palatine Tonsil; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D008934:Mitogens; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate