Suppression of acute experimental inflammation by antisense oligonucleotides targeting secretory phospholipase A2 (sPLA2) in vitro and in vivo experiments.

In HepG2 cells phosphorothioate modified antisense oligonucleotides against a sequence in the Ca2+ binding domain (AS-Ca2+) of type II sPLA2 mRNA restrained IL-6-induced synthesis of sPLA2 protein, sPLA2 mRNA (northern blot), and abolished IL-6 stimulated PGE2 release. An antisense oligonucleotide corresponding to a sequence in the catalytic domain (AS-Cat) of sPLA2 was less effective. The antisense oligonucleotides did not affect albumin synthesis in HepG2 cells, additionally demonstrating their specificity. The corresponding AS-Ca2+ against a homologous part of the rat sPLA2 mRNA depressed rat carrageenin oedema for 60-70%. Identical suppression was achieved by specific low molecular weight inhibitors of sPLA2. Since cyclo- and 5-lipoxygenase inhibitors exerted similar reductions of carrageenin oedema type II sPLA2 dependent eicosanoid formation seems to be a key cascade in this type of inflammation.