| Autor: |
D, Hawkins Lynn, T, Ishizaka Sally, Pamela, McGuinness, Huiming, Zhang, Wendy, Gavin, Bruce, DeCosta, Zhaoyang, Meng, Hu, Yang, Maureen, Mullarkey, W, Young Donna, Hua, Yang, P, Rossignol Daniel, Anneliese, Nault, Jeffrey, Rose, Melinda, Przetak, C, Chow Jesse, Fabian, Gusovsky |
| Zdroj: |
The Journal of Pharmacology and Experimental Therapeutics; February 2002, Vol. 300 Issue: 2 p655-61, 7p |
| Abstrakt: |
A series of novel, synthetic compounds containing lipids linked to a phosphate-containing acyclic backbone are shown to have similar biological properties to lipopolysaccharide (LPS). These compounds showed intrinsic agonistic properties when tested for their ability to stimulate tumor necrosis factor-alpha in human whole blood and interleukin-6 in U373 human glioblastoma cells without added LPS coreceptor CD14. The presence of the LPS antagonist E5564 completely blocked responses, suggesting that the novel compounds and LPS share a common mechanism of cell activation. Stereoselectivity of the molecules was observed in vitro; compounds with an R,R,R,R-configuration were strongly agonistic, whereas compounds with an R,S,S,R-configuration were much weaker in their activity on human whole blood and U373 cells. We also tested the effect of the compounds in cells transfected with the LPS receptor Toll-like receptor 4 (TLR4), with similar results, further supporting a shared mechanism with LPS. This was confirmed in vivo where the agonists failed to elicit cytokine responses in C3H/HeJ mice lacking TLR4 signaling. Because LPS-like molecules enhance immune responses, the compounds were mixed with tetanus toxoid and administered to mice in an immunization protocol to test for adjuvant activity. They enhanced the generation of specific antibodies against tetanus toxoid. Our results indicate that these unique compounds behave as agonists of TLR4, resulting in responses similar to those elicited by LPS. They display adjuvant activity in vivo and may be useful for the development of vaccine therapies. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
