Evidence that glucocorticosteroid-mediated immunosuppressive effects do not involve altering second messenger function.
The mechanism by which glucocorticosteroids (GCS) suppress proliferation of human peripheral blood mononuclear leukocytes (PBML) was investigated. Using the proliferative responses to immobilized anti-CD3 mAb or mitogens (PHA + PMA) as biological readouts, dexamethasone (DEX) and 6 alpha-methylprednisolone (6 alpha-MP) were shown to inhibit PBML proliferation in a concentration-dependent fashion. The mechanism by which GCS mediate immunosuppression did not involve interference with Ca2+ fluxes as: (1) DEX failed to block Ca2+ entry into anti-CD3 + PMA stimulated cells; and (2) Ca2+ ionophores (ionomycin and A23187) failed to circumfent DEX-mediated suppression. DEX also had no effect on protein kinase C (PKC) activity as: (1) inhibitors (H-7 and staurosporin) or stimulators (1,2-dihexanoyl-sn-glycerol [DiC6] and 1,2-dioctanoyl-rac-glycerol [DiC8]) of PKC did not prevent DEX-mediated suppression; (2) DEX did not affect the activation-induced upregulation of CD4 and CD8 expression, an indirect index of PKC activity; and (3) DEX did not alter the activation-associated translocation of PKC from cytosolic to membrane-bound compartments. This, in addition to previous results demonstrating that GCS directly inhibit cytokine gene transcription and that rII-1 + rIL-6 + rIFN-gamma completely abrogated GCS-mediated suppressive effects, further supports the notion that GCS exert their immunosuppressive effects through inhibition of cytokine gene expression.
Almawi
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Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Hadro
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Strom
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D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008775:Methylprednisolone / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D005938:Glucocorticoids; D010835:Phytohemagglutinins; D015759:Ionomycin; D003907:Dexamethasone; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D008775:Methylprednisolone