Endotoxin-mimetic effect of antibodies against Toll-like receptor 4

Citation
J. Nattermann et al., Endotoxin-mimetic effect of antibodies against Toll-like receptor 4, J ENDOTOX R, 6(3), 2000, pp. 257-264
Citations number
24
Categorie Soggetti
Immunology
Journal title
JOURNAL OF ENDOTOXIN RESEARCH
ISSN journal
09680519 → ACNP
Volume
6
Issue
3
Year of publication
2000
Pages
257 - 264
Database
ISI
SICI code
0968-0519(2000)6:3<257:EEOAAT>2.0.ZU;2-2
Abstract
Monospecific, affinity-purified polyclonal antibodies reacting with the ami no-terminal half of the mouse Toll-like receptor 4 (Tlr4) ectodomain failed to block LPS effects and, to the contrary, were capable of inducing TNF sy nthesis when applied to mouse macrophages and cross-linked with a secondary antibody. This effect was observed with macrophages derived from C3H/HeN a nd C57BL/10ScSn mice, but not with macrophages derived from C3H/HeJ or C57B L/10ScCr mice, indicating a specific, Tlr4-dependent effect. Neither primar y nor secondary antibody caused any response if administered in the absence of the other reagent, nor was any response observed in cells from mice lac king Tlr4, or bearing the Lps(d) mutation of Tlr4. These findings support s everal conclusions. Tlr4, the essential transducer of LPS responses, may ac t independently of LPS itself. LPS needs not be internalized, nor must it b ind to a secondary target within the cell in order to exert its effect; rat her, the receptor alone is required for initiation of a signal. The data ar e consistent with the hypothesis that a conformational change in Tlr4 is re quired for activation via this receptor, and reveal that the amino-terminal half of the Tlr4 ectodomain is a target sufficient for antibody-mediated a ctivation.