Cyclosporin A, but not FK506, increases arachidonic acid release and inhibits proliferation of pituitary corticotrope tumor cells.
The selective immunosuppressants cyclosporin A (CsA) and tacrolimus (FK506) are used in the prevention of allogenic transplant rejection and in the therapy of chronic autoimmune inflammatory pathologies. Chronic treatment with CsA leads to secondary functional and trophic alterations of multiple organs and cell systems among which endocrine ones, through insofar uncharacterized mechanisms. With the recent use of FK506 there have been reports of an improved therapeutic efficacy and a reduction of side-effects, as compared to CsA. An intriguing hypothesis is that toxic damage could be due to a systemic CsA activation of arachidonic acid (AA) metabolism, through pathways as yet only partially characterized. The side-effects of both drugs have been poorly studied on cells from tissues other than blood or kidney. We have thus proceeded to study their action on AA release in corticotropic AtT-20/D16-16 cells. The results obtained are as follows: 1) during incubation times > or =12 h, basal AA release is increased by CsA, but not FK506; the acute effect (10 min) of melittin, a PLA2 activator, is significantly potentiated starting from a 30 min pretreatment with CsA but not FK506; manoalide, a PLA2 inhibitor, antagonizes the melittin potentiation of AA release by CsA whereas the inhibition of the melittin stimulus by glucocorticoids is antagonized both by CsA and FK506. 2) during longer (>2 d) incubation times, cell growth is inhibited by CsA but not FK506. These results indicate a role for CsA, not apparent for FK506, in the activation of PLA2 and in the inhibition of cell growth. They also suggest that CsA does not have a direct (i.e. not mediated by the immune system) therapeutic effect in inflammatory processes.
Pompeo
A
A
Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, S. Maria Imbaro (Chieti), Italy. pompeo@cmns.mnegri.it
Baldassare
M
M
Luini
A
A
Buccione
R
R
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004072:Digitonin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D008555:Melitten / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016559:Tacrolimus / Q000009:adverse effects / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D008555:Melitten; D016718:Arachidonic Acid; D003907:Dexamethasone; D016572:Cyclosporine; C045673:manoalide; D010741:Phospholipases A; D054467:Phospholipases A2; D004072:Digitonin; D016559:Tacrolimus