CYCLOSPORINE-A AND FK506 REDUCE INTERLEUKIN-5 MESSENGER-RNA ABUNDANCEBY INHIBITING GENE-TRANSCRIPTION

The cytokine interleukin-5 (IL-5) selectively induces the proliferatio n, differentiation, and activation of mature eosinophils. The immunosu ppressive agents cyclosporin A (CsA) and FK506 ameliorate the influx o f eosinophils seen in allergic conditions such as asthma. We investiga ted the mechanisms controlling IL-5 messenger RNA (mRNA) expression in human T-lymphocytes in the presence of CsA or FK506. Fresh human peri pheral blood mononuclear. cells (PBMC); 7-day cultured PBMC, which rep resent a population of activated T-lymphocytes derived from PBMC; and the T-cell line HSB-2 were used. A novel polymerase chain reaction (PC R)-based nuclear run-on assay was employed to investigate the rate of IL-5 gene transcription. IL-5 mRNA degradation was measured by quantit ative reverse transcriptase (RT)-PCR. CsA and FK506 strongly inhibited cellular IL-5 mRNA expression in response to phytohemagglutinin (PHA) , or to phorbol myristate acetate (PMA), and/or calcium ionophore. Mar ked inhibition was observed in PBMC, 7-day cultured PBMC, and HSB-2 ce lls. Nuclear run-on assays done with either 7-day cultured PBMC or HSB -2 cells demonstrated striking inhibition of IL-5 gene transcription b y both CsA and FK506 at levels reflecting the degree of reduction of t otal cellular IL-5 mRNA abundance. Neither CsA or FK506 had any detect able effect on the stability of IL-5 mRNA. Thus, the inhibitory effect of CsA and FK506 on cellular IL-5 mRNA expression can be explained by inhibition of the rate of IL-5 gene transcription.