Arachidonic acid lipoxygenation may be involved in interleukin-1 induction of prostaglandin biosynthesis.
The induction of prostaglandin (PG) biosynthesis by human recombinant interleukin-1 beta (hrIL-1 beta) has been investigated using rat-isolated stomach strip preparations. hrIL-1 beta (30 and 120 pM) increased CaCl2 responses in a dose-dependent manner with both concentrations significantly potentiating maximum contraction (62.4 +/- 5.1 and 184.2 +/- 36.9%, respectively). This enhancement was characterized further using inhibitors of arachidonic acid metabolism, mRNA and protein synthesis as well as a selective leukotriene (LT) D4 antagonist. Indomethacin (5.6 microM) reduced CaCl2 contractions in the presence of hrIL-1 beta (30 pM) such that only a small residual response was evident, this being reduced further by NDGA (20 microM). Contrastingly, nordihydljroguaiaretic acid reduced only the enhancement of response due to hrIL-1 beta. These findings, supported by parallel radio-immunoassay of PGE2 in the bathing medium after drug treatments suggest strongly that the augmentation of contraction by hrIL-1 beta is due mainly to increased production of PGs. Furthermore, this enhancement is inhibited in a dose-dependent manner by the LTD4 antagonist FPL55712. Additionally, using actinomycin-D and cycloheximide we demonstrated that the hrIL-1 beta induced potentiation is dependent upon mRNA and protein biosynthesis as both compounds substantially reduced responses in the presence of the interleukin. These results provide possible evidence that hrIL-1 beta induced PG production is mediated by a lipoxygenase product, most likely LTD4, which in turn could be important for the induction of de novo protein synthesis.
Mugridge
K G
KG
Sclavo Research Centre, Laboratory of Pharmacology, Siena, Italy.
Donati
D
D
Silvestri
S
S
Parente
L
L
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002122:Calcium Chloride / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008084:Lipoxygenase / Q000502:physiology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000502:physiology
D001095:Arachidonic Acids; D007375:Interleukin-1; D011453:Prostaglandins; D013189:SRS-A; D016718:Arachidonic Acid; D009637:Masoprocol; D008084:Lipoxygenase; D002122:Calcium Chloride; D007213:Indomethacin