What interleukin (IL) does Cyclosporin A (Cyclosporine) inhibit the production of?

Cyclosporin A Inhibits the Production of Interleukin-2

Cyclosporin A primarily inhibits the production of interleukin-2 (IL-2), making option (b) interleukin-2 the correct answer. 1

Mechanism of Action of Cyclosporin A

• Cyclosporin A is a calcineurin inhibitor that suppresses the immune response by down-regulating the transcription of various cytokine genes, with interleukin-2 (IL-2) being the most significant target 1
• The drug binds to cytoplasmic cyclophillin (a cis-trans isomerase) and inhibits calcineurin phosphatase, which prevents the dephosphorylation of nuclear factor of activated T cells (NFAT) 1
• This inhibition prevents NFAT from entering the nucleus and promoting the transcription of lymphokines, most notably IL-2 1

Specific Effects on Cytokine Production

• Cyclosporin A most potently inhibits IL-2 production, which serves as the major activation factor for T-cells in numerous immunological processes 1, 2
• While cyclosporin can affect other cytokines to varying degrees, its primary and most significant effect is on IL-2 1, 2
• The FDA drug label specifically states that cyclosporin "inhibits lymphokine production and release, including interleukin-2 or T-cell growth factor (TCGF)" 2

Effects on Other Cytokines

• Cyclosporin A has some effects on other cytokines but these are generally less pronounced than its effect on IL-2:
  • It has modest decreases in AP-3 and NF-kB activity, which can affect production of other cytokines 3
  • It can inhibit cytokine production from both T-helper 1 (Th1) and T-helper 2 (Th2) cells 1
  • It has some inhibitory effects on tumor necrosis factor-α (TNF-α) production, but this is not its primary mechanism 1
  • Effects on IL-1 and IL-6 are less significant compared to its effect on IL-2 4, 3

Clinical Significance

• The inhibition of IL-2 by cyclosporin A leads to reduced T-helper cell function, which is the main target of the drug's immunosuppressive action 1, 2
• A further effect of IL-2 inhibition is a reduction in B-cell activation and subsequent antibody production 1
• IL-2 levels are known to increase during proteinuria and normalize during remission in adults with idiopathic nephrotic syndrome, making cyclosporin's IL-2 inhibition clinically relevant in these conditions 1

Molecular Basis for IL-2 Inhibition

• At the molecular level, cyclosporin A specifically inhibits the appearance of DNA binding activity of NF-AT, which is critical for IL-2 gene transcription 5
• This inhibition occurs early in the T cell activation cascade, preventing the transcription of the IL-2 gene 3, 6
• The drug acts within minutes of cell stimulation to block the nuclear translocation of transcription factors required for IL-2 gene expression 6