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The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE 2 and TNFα release from human peripheral blood mononuclear cells
Author(s) -
Sudlow Allan W.,
Carey Frank,
Forder Robert,
Rothwell Nancy J.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15305.x
Subject(s) - peripheral blood mononuclear cell , prostaglandin e2 , endocrinology , tumor necrosis factor alpha , medicine , lipopolysaccharide , annexin a1 , chemistry , polyclonal antibodies , cytokine , annexin , microbiology and biotechnology , biology , antibody , immunology , in vitro , biochemistry
1 Lipocortin‐1 and its N‐terminal derivatives exert potent inhibitory actions in various models of acute inflammation. The present study examined the ability of lipocortin (LC)‐1 to suppress the release of the acute pro‐inflammatory mediators, tumour necrosis factor (TNFα) and prostaglandin E 2 (PGE 2 ) from human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) or recombinant human interleukin‐1β (rhIL‐1β). 2 LPS (10 μg ml −1 )‐stimulated release of TNFα and PGE 2 from PBMC was significantly inhibited by (4 h) co‐incubation of the cells with 10 −6 m dexamethasone (Dex), but not with 10 −9 m to 10 −7 m of a N‐terminal fragment (amino acids 1–188) of recombinant human LC‐1 (LC‐1 fragment). However, Dex suppression of LPS‐stimulated TNFα and PGE 2 secretion from PBMC was reversed when polyclonal antibody to LC‐1 fragment (1:10,000 dilution) was included in the medium. rhIL‐1β (5times10 −8 m )‐stimulated release of TNFα and PGE 2 from PBMC (after 18 h) was abolished by co‐incubation of the cells with 10 −7 m LC‐1 fragment. 3 After incubation with Dex (4 h), cellular proteins from PBMC were immunoblotted using anti‐LC‐1 fragment antibody (which showed no cross‐reactivity with human annexins 2 to 6). Dex caused no increase in immunoreactive (ir)LC‐1 content of PBMC, although there was a three fold increase in the amount of a lower mass species with LC‐1‐like immunoreactivity. This was accompanied by the appearance of irLC‐1 in the extracellular medium. 4 The results of the present study implicate endogenous LC‐1 in glucocorticoid suppression of TNFα and PGE 2 release from human PBMC and suggest an extracellular site of action for LC‐1. LC‐1 may also inhibit rhIL‐1β‐stimulated TNFα and PGE 2 secretion from PBMC.