Cyclosporin A, but not FK506, increases arachidonic acid release and inhibits proliferation of pituitary corticotrope tumor cells

A Pompeo, Massimiliano Baldassarre, A Luini, R Buccione, Massimiliano Baldassarre

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)837-46
Number of pages10
JournalLife Sciences
Volume64
Issue number10
Publication statusPublished - 1999

Fingerprint

Pituitary Neoplasms
Tacrolimus
Arachidonic Acid
Cyclosporine
Tumors
Cells
Melitten
Cell growth
Chemical activation
Transplants
Immune system
Poisons
Graft Rejection
Therapeutic Uses
Pathology
Immunosuppressive Agents
Growth
Drug-Related Side Effects and Adverse Reactions
Metabolism
Glucocorticoids

Keywords

  • Animals
  • Arachidonic Acid
  • Cell Division
  • Cell Size
  • Cell Survival
  • Cyclosporine
  • Dexamethasone
  • Digitonin
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Immunosuppressive Agents
  • Interleukin-1
  • Melitten
  • Mice
  • Phospholipases A
  • Phospholipases A2
  • Pituitary Neoplasms
  • Tacrolimus
  • Terpenes
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha
  • Vitamin E

Cite this

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title = "Cyclosporin A, but not FK506, increases arachidonic acid release and inhibits proliferation of pituitary corticotrope tumor cells",
abstract = "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.",
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author = "A Pompeo and Massimiliano Baldassarre and A Luini and R Buccione and Massimiliano Baldassarre",
year = "1999",
language = "English",
volume = "64",
pages = "837--46",
journal = "Life Sciences",
issn = "0024-3205",
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TY - JOUR

T1 - Cyclosporin A, but not FK506, increases arachidonic acid release and inhibits proliferation of pituitary corticotrope tumor cells

AU - Pompeo, A

AU - Baldassarre, Massimiliano

AU - Luini, A

AU - Buccione, R

AU - Baldassarre, Massimiliano

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

KW - Animals

KW - Arachidonic Acid

KW - Cell Division

KW - Cell Size

KW - Cell Survival

KW - Cyclosporine

KW - Dexamethasone

KW - Digitonin

KW - Dose-Response Relationship, Drug

KW - Enzyme Activation

KW - Immunosuppressive Agents

KW - Interleukin-1

KW - Melitten

KW - Mice

KW - Phospholipases A

KW - Phospholipases A2

KW - Pituitary Neoplasms

KW - Tacrolimus

KW - Terpenes

KW - Time Factors

KW - Tumor Cells, Cultured

KW - Tumor Necrosis Factor-alpha

KW - Vitamin E

M3 - Article

C2 - 10096434

VL - 64

SP - 837

EP - 846

JO - Life Sciences

JF - Life Sciences

SN - 0024-3205

IS - 10

ER -