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Protosappanin A induces immunosuppression of rats heart transplantation targeting T cells in grafts via NF-kappaB pathway.

Abstract
Protosappanin A as one major and effective ingredient from Caesalpinia sappan L. exhibited antirejection activity obviously in heart-transplanted rat. The present study was designed to screen out the potential target genes of protosappanin A with microarray technology and reveal some molecular mechanism of immunosuppressive effect. Rats performed with ectopic peritoneal heart transplantation were randomized into three groups receiving different treatments for 7 days: protosappanin A group (25 mg kg(-1)), cyclosporine A group (10 mg kg(-1)), and control group. The differentially expressed genes responding to protosappanin A were analyzed with microarrays. Among common differentially expressed genes, the ones of interest were selected for further evaluation by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), Western blot, immunochemistry, immunofluorescence, and ELISA. Among the 146 common differentially expressed genes, NF-kappaB and related genes like IkappaBa, IFN-r, and IP10 were selected for verification. The results of qRT-PCR, Western blot, immunochemistry, and ELISA showed that protosappanin A significantly reduced the expression of NF-kappaB, IFN-r, and IP10 (p < 0.05) and increased IkappaBa expression (p < 0.05) in graft. Moreover, the immunochemistry staining of NF-kappaB and IkappaBa was mainly observed in infiltrating mononuclear cells. Strikingly, immunofluorescent staining localized NF-kappaB to the TCR-positive T cells in graft. Furthermore, protosappanin A exhibited inhibitory effect on T cell proliferation in recipients after 7-day treatment. In conclusion, protosappanin A might act on T cells through inhibiting NF-kappaB activation and downstream gene expressions of IFN-r and IP10, meanwhile reducing T cell proliferation responding to alloantigen, so as to induce immunosuppressive effect. The results encourage a potential therapeutic evaluation of protosappanin A for clinical organ transplantation or other T cell-mediated immune disorders. Additionally, our study also verified the feasibility of microarray utilization in Chinese herb research to explore molecular mechanism and promote development of scientific theories.
AuthorsJian Wu, Maomao Zhang, Haibo Jia, Xingtao Huang, Qi Zhang, Jingbo Hou, Yu Bo
JournalNaunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 381 Issue 1 Pg. 83-92 (Jan 2010) ISSN: 1432-1912 [Electronic] Germany
PMID19924402 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Drugs, Chinese Herbal
  • Immunosuppressive Agents
  • NF-kappa B
  • Phenols
  • protosappanin A
Topics
  • Animals
  • Caesalpinia
  • Drug Delivery Systems (methods)
  • Drugs, Chinese Herbal (administration & dosage)
  • Graft Survival (drug effects, immunology)
  • Heart Transplantation (immunology, pathology)
  • Immunosuppressive Agents (administration & dosage)
  • Male
  • NF-kappa B (antagonists & inhibitors, physiology)
  • Phenols (administration & dosage)
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Signal Transduction (drug effects, immunology)
  • T-Lymphocytes (drug effects, immunology, metabolism)

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