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Evidence that glucocorticosteroid-mediated immunosuppressive effects do not involve altering second messenger

W Y Almawi1, E T Hadro, T B Strom

  • 1Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Transplantation
|July 1, 1991
PubMed

Insights

Glucocorticosteroids (GCS) suppress human leukocyte proliferation by inhibiting cytokine gene expression, not by affecting calcium or protein kinase C pathways. This mechanism underlies GCS-mediated immunosuppression.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Glucocorticosteroids (GCS) are potent immunosuppressants.
  • The precise molecular mechanisms underlying GCS-mediated immunosuppression require further elucidation.

Purpose of the Study:

  • To investigate the mechanism by which GCS suppress human peripheral blood mononuclear leukocyte (PBML) proliferation.
  • To determine if GCS interfere with calcium (Ca2+) fluxes or protein kinase C (PKC) activity during immunosuppression.

Main Methods:

  • Assessed PBML proliferation responses to anti-CD3 mAb and mitogens (PHA + PMA).
  • Evaluated the effects of dexamethasone (DEX) and 6 alpha-methylprednisolone (6 alpha-MP) on Ca2+ entry and ionophore-induced proliferation.
  • Measured PKC activity using inhibitors, stimulators, and cell surface marker expression (CD4, CD8).
  • Examined PKC translocation from cytosolic to membrane compartments.

Main Results:

  • Dexamethasone (DEX) and 6 alpha-methylprednisolone (6 alpha-MP) inhibited PBML proliferation concentration-dependently.
  • GCS did not interfere with Ca2+ fluxes into stimulated cells.
  • GCS did not affect PKC activity, including activation-induced marker upregulation and subcellular translocation.
  • Previous findings indicate GCS inhibit cytokine gene transcription, and cytokine addition abrogated GCS suppression.

Conclusions:

  • GCS-mediated immunosuppression of PBML proliferation does not involve interference with Ca2+ signaling or PKC activity.
  • The primary mechanism of GCS immunosuppression is the inhibition of cytokine gene expression.
  • These findings reinforce the understanding of GCS's role in regulating immune responses.

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