Combination therapy of cyclosporine with steroid inhibits gamma-interferon and interleukin-1 gene expression at the level of mRNA synthesis in vivo.

The present study examined the effect of cyclosporine (CsA) administered with steroid in vivo on the capacity of peripheral blood mononuclear cells (PBMC) from kidney transplant recipients to generate cytokines and their gene expression at the level of messenger RNA (mRNA). PBMC from CsA-prednisolone (Pred)-treated recipients displayed 66.9% inhibition (54.3 +/- 12.4 IU/ml; N = 42; P less than 0.01) of gamma-interferon (gamma-IFN) production compared with normal individuals (134.6 +/- 18.6 IU/ml; N = 23). Azathioprine (Az)-Pred-treated recipients displayed significantly less inhibition of gamma-IFN generation (96.0 +/- 16.1 IU/ml; N = 22; P less than 0.05) than CsA-treated patients. Macrophages (m phi) from CsA-Pred-treated recipients displayed 60.0% inhibition (5.1 +/- 0.7 U/ml; N = 20; P less than 0.01) of interleukin-1 (IL-1) production compared with normal individuals (13.0 +/- 2.9 U/ml; N = 21). These results were confirmed by the experiments using cDNA probe for gamma-IFN or IL-1 (alpha, beta). High levels of gamma-IFN mRNA in phytohemagglutinin (PHA)-stimulated PBMC or IL-1(beta) mRNA in lipopolysaccharide (LPS)-stimulated m phi were present in normal individuals but not in CsA-treated recipients as judged by hybridization to a cloned human gamma-IFN or IL-1(beta) cDNA probe. These studies demonstrated that combination therapy of CsA with steroid inhibits both gamma-IFN and IL-1 gene expression at the level of mRNA at physiological concentrations.