Plant alkaloid tetrandrine downregulates I κ B α kinases‐I κ B α ‐NF‐ κ B signaling pathway in human peripheral blood T cell

Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han‐Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28‐costimulated T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF‐ κ B) transcription factors, critical in CD28 costimulation, in Tet‐mediated immunosuppression in human peripheral blood T cells. We showed that Tet inhibited NF‐ κ B DNA‐binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28‐costimulated NF‐ κ B activities. Since Tet itself did not affect NF‐ κ B binding to its corresponding DNA sequence, the results suggested that Tet might regulate NF‐ κ B upstream signaling molecules. Further studies demonstrated that Tet could prevent the degradation of I κ B α and inhibit nuclear translocation of p65 by blocking I κ B α kinases α and β activities. In addition, the activation of mitogen‐activated protein kinases such as c‐jun N‐terminal kinase, p38 and extracellular signal‐regulated kinase and activator protein‐1 DNA‐binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF‐ κ B transcriptional activity by Tet. When four Tet analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28‐costimulated but not on H 2 O 2 ‐induced NF‐ κ B DNA‐binding activities. Our results provide the molecular basis of immunomodulation of Tet for being a potential disease‐modifying antirheumatic drug in the therapy of autoimmune disorders like rheumatoid arthritis.British Journal of Pharmacology (2004) 143 , 919–927. doi: 10.1038/sj.bjp.0706000