title: Evidence that glucocorticosteroid-mediated immunosuppressive effects do not involve altering second messenger function.
abstract: 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.
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: W Y
authors.initials: WY
authors.lastname: Almawi
authors.forename: E T
authors.initials: ET
authors.lastname: Hadro
authors.forename: T B
authors.initials: TB
authors.lastname: Strom
mesh_terms: 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
chemical_list: 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