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.
Tibes
U
U
Boehringer Mannheim GmbH, Dept. of Preclinical Research, Mannheim.
Röhr
S P
SP
Scheuer
W
W
Amandi-Burgermeister
E
E
Litters
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A
D000085:Acetates / Q000494:pharmacology; D000418:Albumins / Q000096:biosynthesis; D000818:Animals; D001483:Base Sequence; D001578:Benzopyrans / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004487:Edema / Q000201:enzymology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000201:enzymology / Q000517:prevention & control*; D015850:Interleukin-6 / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics* / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000235:genetics*; D054467:Phospholipases A2; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000085:Acetates; D000418:Albumins; C405509:BM 16.2266; D001578:Benzopyrans; D017931:DNA Primers; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D002351:Carrageenan; D010741:Phospholipases A; D054467:Phospholipases A2