The role of lipocortin‐1 in dexamethasone‐induced suppression of PGE₂ and TNFα release from human peripheral blood mononuclear cells

Abstract

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 E2 (PGE2) from human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) or recombinant human interleukin‐1β (rhIL‐1β). LPS (10 μg ml−1)‐stimulated release of TNFα and PGE2 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 PGE2 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 PGE2 from PBMC (after 18 h) was abolished by co‐incubation of the cells with 10−7 m LC‐1 fragment. 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. The results of the present study implicate endogenous LC‐1 in glucocorticoid suppression of TNFα and PGE2 release from human PBMC and suggest an extracellular site of action for LC‐1. LC‐1 may also inhibit rhIL‐1β‐stimulated TNFα and PGE2 secretion from PBMC.

Opposing influences of glucocorticoids and interleukin‐1β on the secretion of growth hormone and ACTH in the rat in vivo: role of hypothalamic annexin 1

“…Similar conclusions may be drawn from our observation that, when given centrally, annexin 1 Ac2 ± 26 mimics the inhibitory actions of corticosterone on HPA function, thereby producing a dose-dependent inhibition of the ACTH response to i.c.v. injection of IL-1b, and from previous studies by ourselves and others using annexin 1 1 ± 346 and annexin 1 1 ± 188 (Loxley et al, 1993a;Sudlow et al, 1996). In line with studies on other tissues/systems (Harris et al, 1995;Croxtall et al, 1998;John et al, 1998) the dose of annexin 1 Ac2 ± 26 required to produce a measurable response was considerably higher than that of either annexin 1 1 ± 346 or annexin 1 1 ± 188 (Loxley et al, 1993b).…”

Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice

“…This phenomenon can be correlated to the inhibition of pro-fibrotic cytokine generation such as TGF-β and TNF-α. Previous studies showed that ANXA1 has a regulatory effect on the production of inflammatory cytokines such as TNF-α and IL-1β through inhibition of NF-κB activation (Sudlow et al, 1996;D'Acquisto et al, 1997). In line with this observation, ANXA1 and the derived peptide Ac2-26 were shown to suppress proliferation and activation of the human epithelial cell line A 549 (Croxtall et al, 1998b).…”

An overview of the effects of annexin 1 on cells involved in the inflammatory process

“…There are numerous studies establishing that macrophage-derived inflammatory mediators can be inhibited by GC in an ANXA1-dependent manner by the application of immunoneutralisation strategies, including TNF-α and PGE 2 release from human PBMC (Sudlow et al 1996) and nitric oxide generation by rat synovial macrophages (Yang et al 1998). In a single study, human recombinant ANXA1, as well as ANXA1 purified from human peripheral blood mononuclear cells (PBMC) or mouse lung inhibited iono- (1) is observed when a pro-inflammatory phase of inflammation is followed by an active phenomenon of resolution.…”