Plant alkaloid tetrandrine downregulates IκBα kinases-IκBα- NF-κB signaling pathway in human peripheral blood T cell.

1 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. 2 We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulaied T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-κB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. 3 We showed that Tel inhibited NF-κB 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-κB activities. Since Tet itself did not affect NF-κB binding lo its corresponding DNA sequence, the results suggested that Tet might regulate NF-κB upstream signaling molecules. 4 Further studies demonstrated that Tet could prevent the degradation of IκBα and inhibit nuclear translocation of p65 by blocking IκBα kinases α and β activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signalregulated 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-κB transcriptional activity by Tet. 5 When four Tel analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-coslimulaled but not on H₂O₂-induced NF-κB DNA-binding activities. 6 Our results provide the molecular basis of immunomodulation of Tet for being a potential diseasemodifying antirheumalic drug in the therapy of autoimmune disorders like rheumatoid arthritis. [ABSTRACT FROM AUTHOR]