Blocking effect of an immuno-suppressive agent, cynarin, on CD28 of T-cell receptor.
OBJECTIVE
Cynarin, a potential immunosuppressant that blocks the interaction between the CD28 of T-cell receptor and CD80 of antigen presenting cells, was found in Echinacea purpurea by a new pharmaceutical screening method: After Flowing Through Immobilized Receptor (AFTIR; Dong et al., J Med Chem, 49: 1845-1854, 2006). This Echinacea component is the first small molecule that is able to specifically block "signal 2" of T-cell activation.


METHODS
In this study, we used the AFTIR method to further confirm that cynarin effectively blocked the binding between CD80 of B-cells and CD28 of T-cells, and provide details of its mechanism of action.


RESULTS
The experimental results showed that cynarin blocked about 87% of the CD28-dependent "signal 2" pathway of T-cell activation under the condition of one to one ratio of T-cell and B-cell in vitro. Theoretical structure modeling showed that cynarin binds to the "G-pocket" of CD28 (Evans et al., Nat Immunol, 6:271-279, 2005), and thus interrupts the site of interaction between CD28 and CD80.


CONCLUSIONS
These results confirm both that AFTIR is a promising method for screening selective active compounds from herbal medicine and that cynarin has great potential as an immuno-suppressive agent.
Dong
Guo-Chung
GC
Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 115, Taiwan.
Chuang
Ping-Hsien
PH
Chang
Kai-chun
KC
Jan
Pey-shynan
PS
Hwang
Pei-Ing
PI
Wu
Huan-Bin
HB
Yi
Myunggi
M
Zhou
Huan-Xiang
HX
Chen
Hueih Min
HM
D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D001665:Binding Sites; D018106:CD28 Antigens / Q000737:chemistry / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D002934:Cinnamates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018920:Coculture Techniques; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D020900:Echinacea / Q000737:chemistry; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D018122:B7-1 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; D002934:Cinnamates; C508594:IL2 protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C100257:cynarine