Lipocortin 1 fragment modifies pyrogenic actions of cytokines in rats

Abstract

Lipocortins form a group of proteins that have been proposed as mediators of the anti-inflammatory actions of glucocorticoids. Intracerebroventricular injection of a recombinant fragment of lipocortin 1 (NH2-terminal 1-188) caused dose-dependent (0.4-1.2 micrograms) reductions in the acute increases in colonic temperature and oxygen consumption, which occurred in response to central injections of recombinant interleukin 1 beta and gamma-interferon in conscious rats. In contrast the lipocortin fragment did not affect the response to prostaglandin E2, and its activity was prevented by heat treatment or by pretreatment of animals with polyclonal antiserum raised to the fragment. Central injection of antiserum significantly enhanced the thermogenic responses to interleukin 1 beta in rats treated with dexamethasone without affecting the responses in normal animals. These results support a physiological role for lipocortin in the central effects of glucocorticoids.

The local anti‐inflammatory action of dexamethasone in the rat carrageenin oedema model is reversed by an antiserum to lipocortin 1

“…Data described in this paper using this approach strongly suggest that the acute local anti-inflammatory action of dexamethasone is at least partially dependent upon the generation of lipocortin 1. Carey et al (1990) were able successfully to demonstrate that the same antiserum as was used in this study, reversed the action of dexamethasone as an anti-pyretic agent in the rat. Lipocortin 1 itself was active as an antipyretic in this model.…”

“…This indeed is congruent with other evidence. For example the external application of lipocortin to cells or its intravenous administration to animals (Cirino et al, 1989;Carey et al, 1990;Davidson et al, 1991) produces a prompt and dramatic effect on eicosanoid generation, inflammation or fever. Furthermore, the existence of a protein binding site with a high affinity for lipocortin has been detected on the surface of some human cells with the obvious implication that this is a receptor or a target enzyme (Goulding et al, 1990b).…”

“…The lipocortin antiserum was raised in rabbit to human recombinant lipocortin 1 residues 1-188 which had been expressed in E. coli as previously described (Carey et al, 1990).…”

“…Administration of purified human recombinant lipocortin 1 produces anti-inflammatory and antipyretic effects in rats and rabbits (Cirino et al, 1989;Carey et al, 1990;Davidson et al, 1991), eicosanoid suppressive actions in cells in vitro and ameliorates ischaemic damage (infarct size and cerebral oedema) produced in rat brain by occlusion of the middle cerebral artery (Relton et al, 1991).…”

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

“…A fragment of recombinant human lipocortin-l consisting of amino acids 1-188 (LC-1 fragment) was synthesized as described by Carey et al (1990), and comprised 0.42 mg ml-' protein ( > 99% purity; < 12.5 endotoxin units ml-' in the Limulus lysate assay, TechGen, U.K.) in 25 mM Tris, pH 8. LC-1 fragment was conjugated to bovine thyroglobulin using N-(dimethylaminopropyl)-NA-ethylcarbodiimide, dialysed, concentrated by freeze-drying, reconstituted in adjuvant and injected (intramuscularly) into the hind limb of a New Zealand white rabbit in a manner similar to that described by Forder & Carey (1983).…”