Matrine induces cell anergy in human Jurkat T cells through modulation of mitogen-activated protein kinases and nuclear factor of activated T-cells signaling with concomitant up-regulation of anergy-associated genes expression.
Induction of immunotolerance has become a new strategy for treating autoimmune conditions in recent decades. However, so far there is no ideal therapeutics available for clinical use. Medicinal herbs are a promising potential source of immunotolerance inducers. In the current study, we sought first to optimize conditions for a validated cellular model of human Jurkat cells; and then used this model to screen bioactive compounds derived from medicinal plants for inducing T cell anergy in comparison with the effect of well-known T cell anergy inducer, ionomycin. The results showed that passage of the cells, and concentration and stimulation time of ionomycin on the cells could influence the ability of T cell anergy induction. Matrine, a small molecule derived from the root of Sophora flavescens AIT., was demonstrated to be effective in inducing T cell anergy in human Jurkat cells. The cells exposed to matrine showed markedly decreased mRNA expression of interleukin-2, an indicator of T cell anergy, when the cells were stimulated by antigens, anti-OKT3 plus anti-CD28. Mechanistic study showed that ionomycin and matrine could up-regulate the anergy-associated gene expressions of CD98 and Jumonji and activate nuclear factor of activated T-cells (NFAT) nuclear translocation in absence of cooperation of AP-1 in Jurkat cells. Pre-incubation with matrine or ionomycin could also shorten extracellular signal-regulated kinase (ERK) and suppress c-Jun NH(2)-terminal kinase (JNK) expression on the anergic Jurkat cells when the cells were stimulated with anti-OKT-3 plus anti-CD28 antibodies. Thus, matrine is a strong candidate for further investigation as a T cell immunotolerance inducer.
Li
Ting
T
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
Wong
Vincent Kam Wai
VK
Yi
Xiao Qin
XQ
Wong
Yuen Fan
YF
Zhou
Hua
H
Liu
Liang
L
D000470:Alkaloids / Q000494:pharmacology*; D000941:Antigens / Q000235:genetics / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics; D017635:Clonal Anergy / Q000187:drug effects* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015759:Ionomycin; D007476:Ionophores; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016853:Muromonab-CD3; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D018517:Plant Roots; D011807:Quinolizines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D029909:Sophora / Q000737:chemistry*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1; D015854:Up-Regulation; D000093842:Matrines
D000470:Alkaloids; D000941:Antigens; D007376:Interleukin-2; D007476:Ionophores; D016853:Muromonab-CD3; D050778:NFATC Transcription Factors; D010936:Plant Extracts; D011807:Quinolizines; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D015759:Ionomycin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000093842:Matrines