Antipyretic actions of human recombinant lipocortin‐1

Abstract

The effect of human recombinant lipocortin-1 (hrLC-1) on the pyrogenic actions of the synthetic polyribonucleotide polyinosinic: polycytidylic acid (poly I: C) has been studied in conscious rabbits. Poly I: C (2.5 pg kg-) given i.v. produced a biphasic fever with a first peak after 90-105 min and a second peak between 225-240 min. hrLC-1 (50ougkg-) given i.v. simultaneously with the poly I: C produced a significant reduction in the febrile response but without complete suppression. The thermal response index over 5 h (TRI5) was 4.69 + 0.51 for poly I: C given with saline and the TRI5 for poly I: C given with hrLC-1 was 2.66 + 0.45 (values are for n = 5 + s.e.mean, P < 0.05). hrLC-1 administered alone had no effect on body temperature and its antipyretic activity was lost on heating. In a separate series of experiments 1 h pretreatment with dexamethasone (1 mgkg -) given i.v. reduced the pyrogenic response (TRI5) to poly I: C (2.5 ug kg-1) from 4.87 + 0.54 without dexamethasone to 2.00 + 0.25 (n = 5, P < 0.05) and dexamethasone given alone had no effect on body temperature. These data demonstrate that LC-1 possesses antipyretic actions and raises the possibility that the antipyretic actions of dexamethasone are mediated through the induction of LC-1.

Glucocorticoid — and non‐glucocorticoid induction of lipocortins (annexins) 1 and 2 in rat peritoneal leucocytes in vivo

“…This pool of lipocortin is significant as Carnuccio et al (1981) and Cirino & Flower (1987b) reported that it is the external membrane-associated lipocortin 1 that produces its biological effects. Furthermore, the models in which lipocortin 1 has been shown to have biological activity are those in which the protein has been applied externally (Cirino & Flower, 1987a;Cirino et al, 1987;Davidson et al, 1991 (Sheets et al, 1987) and in porcine heart (Pula et al, 1990) and A431 cells (Ando et al, 1991). In the first two examples, lipocortin 1, and 5 and 6 respectively could be extracted by non-ionic detergents but not by EGTA, and hence resemble the membrane-bound pools observed in elicited cells.…”

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

“…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).…”

“…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).…”

Modulation of Phagocytosis of Apoptotic Neutrophils by Supernatant from Dexamethasone-Treated Macrophages and Annexin-Derived Peptide Ac2–26

“…Annexin 1 is a glucocorticoid-inducible protein (14) that mediates many of the anti-inflammatory actions of glucocorticoids in models of acute (15) and chronic (16) inflammation including modulation of leukocyte trafficking (17,18), ischemic damage (19), pain (20), and fever (21). Evidence for a functional link between annexin 1 and apoptosis has emerged (22,23).…”

“…As discussed above, annexin 1 protein is up-regulated by glucocorticoids to mediate some of their anti-inflammatory properties (15)(16)(17)(18)(19)(20)(21). We investigated the potential role of endogenous annexin 1 on phagocytosis of apoptotic cells by M. Human monocytes were cultured for 5 days in the presence or absence of 1 M Dex.…”