Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Patent
1988-12-02
1992-05-26
Nucker, Christine
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
514 21, 435 692, 930250, C07K 1506, A61K 3764
Patent
active
051169428
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to protein having an inflammatory phospholipase A.sub.2 (PLA.sub.2) inhibitory activity. More particularly, this invention relates to protein which is induced from cells by the administration of glucocorticoid and has an inflammatory PLA.sub.2 inhibitory activity.
BACKGROUND ART
Glucocorticoid is now widely used as one of the most efficacious medicines against various inflammatory diseases and allergic diseases inclusive of rheumatoid arthritis, lupus erythematosus, and bronchial asthma. The mechanism of its action is attributable to the anti-inflammatory action, anti-edematous action, and immunosuppressive action of glucocorticoid. Of these actions, the mode of anti-inflammatory action relates to the inhibition of the release of arachidonic acid, which is the precursor of prostaglandins or leukotriens regarded to be inflammatory mediators. A new theory has recently been put forward by Flower (Nature 278: 456 (1979)) that glucocorticoid suppresses the activity of PLA.sub.2 which is a key enzyme to release arachidonic acid directly from the phospholipid. With regard to the action mechanism of glucocorticoid, it is understood that, when it enters into a cell, glucocorticoid is first bound to the receptor of the cell, then the resulting complex is translocated into the nucleus to activate the specific gene, finally inducing the synthesis of specific protein. Actually, Tsurufuji et al. have shown (Nature 280: 408 (1979)) that cycloheximide, an inhibitor of protein synthesis and actinomycin D, an inhibitor of mRNA synthesis, suppress the therapeutic effect of glucocorticoid against paw edema (experimental animal model of inflammation) caused by serotonin. Thus, it is suggestive from the above-mentioned results, that glucocorticoid displays its anti-inflammatory activity through the induction of the synthesis of PLA.sub.2 inhibitory protein.
Attempts have hitherto been made by several groups to isolate such a protein whose synthesis is induced by glucocorticoid and that inhibits the activity of PLA.sub.2 in vitro and suppresses the production of prostaglandin in vivo. In these attempts, porcine pancreas PLA.sub.2 is used in their evaluation system. There are, however, another inflammatory PLA.sub.2 having different properties from those of pancreas PLA.sub.2 which has been generally regarded as playing a role of a digestive enzyme. Recently, Inoue et al [Biochemistry (written in Japanese) 58 (No. 8): 766 (1986)] have isolated and purified PLA.sub.2 occurring in rat's peritoneal cavity and investigated its properties. They observed that the inoculation of 100 ng of purified enzyme into the skin of rat backs caused the rise in vascular permeability to leak out Evans blue which had been intravenously injected beforehand. In the meantime, PLA.sub.2 originating from pancreas has not been confirmed to exhibit this activity. Further, Vadas et al reported that PLA.sub.2 in the joints of rheumatoid arthritis is increased and that the purified enzyme does not react with the antibody of human pancreas PLA.sub.2 (J. Biochem. 100, 1297-1030, 1986). Thus, the PLA.sub.2 originating from pancreas differs from the inflammatory PLA.sub.2 in the primary and tertiary structures and their roles in vivo are distinctly different from each other.
DISCLOSURE OF THE INVENTION
Under such backgrounds, the present inventors have made intense search for proteins which specifically inhibiting the enzyme and reached the present invention. The protein according to the present invention is induced from a cell by the administration of glucocorticoid, and particularly preferable protein is purified from the peritoneal cavities after administration of glucocorticoid to a rat and has an inflammatory PLA.sub.2 -inhibitory activity, having a molecular weight of 40 K and an amino acid sequence from the N-terminal consisting of a N-terminal amino acid-Asp-Val-Pro-Ala-Ala-Asp-Leu-Ser-Asp-, or is purified from the peritoneal cavities after administration of glucocorticoid to a rat and has an infl
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Imaizumi Atsushi
Inoue Keizo
Kamimura Takashi
Kudo Ichiro
Okada Masahiro
Kim Kay K.
Nucker Christine
Teijin Limited
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