Rapid non-genomic inhibitory effects of glucocorticoids on human neutrophil degranulation.
BACKGROUND
Glucocorticoids acting as anti-inflammatory or immunosuppressive drugs have been shown to exert most of their effects genomically. Recent findings suggest that non-genomic activity might be relatively more important in mediating the therapeutic effects of high-dose pulsed glucocorticoid. However, few non-genomic anti-inflammatory effects were reported, much less non-genomic mechanisms.


OBJECTIVE
This study was performed to investigate the nongenomic effects of glucocorticoids on human neutrophil degranulation.


METHODS
Purified human neutrophils were pretreated with 6 alpha-methylprednisolone or hydrocortisone for 5 min, and then primed with N-formyl-methionyl-leucyl-phenylalanine (fMLP) (10(-6) M) or phorbol myristate acetate (PMA) (50 ng/ml) in the presence of cytochalasin B. The release of two markers of neutrophil granules, lactoferrin and myeloperoxidase, was measured by ELISA and enzymology methods respectively.


RESULTS
Both 6 alpha-methylprednisolone (10(-5)-10(-4) M) and hydrocortisone (10(-4) M) showed significant inhibitory effects on neutrophil degranulation within 5 min after fMLP administration. For PMA stimulated degranulation, 6 alpha-methylprednisolone (10(-4) M) showed significant inhibitory effects (p < 0.01), while hydrocortisone (10(-4) M) only showed an inhibitory tendency (P > 0.05). Neither RU486 (10(-5) M) nor cycloheximide (10(-4) M) could alter the inhibitory effects of glucocorticoids.


CONCLUSIONS
Our results demonstrate that megadoses of glucocorticoids exert rapid inhibitory effects on human neutrophil degranulation at the cellular level via a new mechanism that is independent of corticosteroid type II receptor occupation or protein synthesis. We infer that these effects may be very important when glucocorticoids act as anti-inflammatory drugs during pulse therapy.
Liu
L
L
Department of Nautical Medicine, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, PR of China.
Wang
Y X
YX
Zhou
J
J
Long
F
F
Sun
H W
HW
Liu
Y
Y
Chen
Y Z
YZ
Jiang
C L
CL
D015550:Cell Degranulation / Q000187:drug effects*; D005786:Gene Expression Regulation; D023281:Genomics; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008775:Methylprednisolone / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D005938:Glucocorticoids; D015735:Mifepristone; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013755:Tetradecanoylphorbol Acetate; D006854:Hydrocortisone; D008775:Methylprednisolone