Premium
Antirheumatic gold compounds and penicillamine enhance protein kinase C‐mediated activation of the arachidonate‐ mobilizing phospholipase A 2 in mouse macrophages
Author(s) -
Bondeson Jan,
Sundler Roger
Publication year - 1993
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.54.4.329
Subject(s) - auranofin , penicillamine , phospholipase a2 , protein kinase c , leukotriene c4 , protein kinase a , calcium , ionophore , biochemistry , leukotriene b4 , phospholipase a , phorbol , chemistry , phospholipase , pharmacology , prostaglandin e , gold sodium thiomalate , biology , phosphorylation , enzyme , leukotriene , immunology , inflammation , rheumatoid arthritis , asthma , organic chemistry
The effects of antirheumatic gold compounds and D‐penicillamine on protein kinase C‐ and Ca 2+ ‐ mediated activation of arachidonate mobilization and the formation of eicosanoids in mouse macrophages have been investigated. Auranofin (0.2‐2 μΜ) enhanced the response to phorbol ester two‐ to three‐fold, and similar enhancement was caused by aurothiomalate, aurothioglu‐ cose, and penicillamine, but only after pretreatment for 1‐4 h. The enhanced mobilization of arachidonate was accompanied by increased formation and release of prostaglandin E 2 and 6‐keto prostaglandin F lα , but not of lipoxygenase metabolites. No such enhancement occurred when the arachidonate‐mobilizing phospholipase A 2 was activated directly (calcium ionophore A23187). Instead, auranofin caused selective inhibition of calcium ionophore‐induced formation of leukotriene C 4 . Treatment of macrophages with 4β‐phorbol 12‐myristate 13‐acetate causes a rapid increase in the phosphorylation and a 1.4‐1.8‐fold increase in the activity of the 85‐kd arachidonate‐mobilizing phospholipase A 2 as determined in an in vitro assay. The increase in activity was further enhanced by both the gold compounds and penicillamine. These findings indicate that the target for the enhancing effect of the antirheumatic drugs is located between protein kinase C and phospholipase A 2 in the signal chain leading to activation of the latter enzyme.