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(5R)-5-hydroxytriptolide inhibits IFN--related signaling

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Abstract

Aim: (5R)-5-hydroxytriptolide (LLDT-8) displayed anti-arthritis and anti-allogenic transplantation rejection activities in our previous studies. Here, we aim to further clarify the effect of LLDT-8 on the pro-inflammatory cytokine IFN-. Methods: T cells were activated with anti-CD3 antibody or concanavalin A (ConA). The expression of cell surface molecules was detected with flow cytometry. Cells were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE) to test cell division. IFN- production was determined by enzyme-linked immunosorbent assay. Cell proliferation was evaluated by [3H]-thymidine uptake. Mice were immunized with ovalbumin to assess the in vivo immune response. RT-PCR and Real-time PCR were applied to determine the mRNA expression. The protein phosphorylation levels were detected by Western immunoblot assay. Results: LLDT-8 at 100 nmol/L did not change the CD25, CD69, and CD154 expressions in anti-CD3-stimulated T cells. LLDT-8 markedly blocked the cell division of CD4 and CD8 T cells after ConA stimulation. LLDT-8 inhibited T cell-derived IFN-. production. Moreover, LLDT-8 suppressed the ovalbumin-specific T cell proliferation and IFN- generation. In anti-CD3-activated T cells, LLDT-8 abrogated the mRNA expression of signal transducer and activator of transcription 1 (STAT1), T-box transcription factor, IL-12 receptor 2, STAT4, and interferon regulatory factor 1 in the IFN- expression pathway. Western blot analysis showed that LLDT-8 blocked the phosphorylation levels of extracellular signal-regulated kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase in anti-CD3 plus anti-CD28-activated T cells. In addition, LLDT-8 reduced the transcripts of macrophage inflammatory protein (Mip)-1α, Mip-1, regulated upon activation normally T-cell expressed and secreted, induc-ible protein-10, IFN-inducible T cell a chemoattractant, and monokine induced by IFN- in IFN--stimulated murine macrophage cell line Raw 264.7 cells. Conclusion: LLDT-8 was a potential inhibitor for IFN--associated signaling.
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Keywords: (5R)-5-hydroxytriptolide; IFN-; MAPK; chemokine

Document Type: Research Article

Affiliations: 1: Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China 2: Laboratory of Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China

Publication date: 2006-12-01

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