ISSN:
1420-908X
Keywords:
Key words: Cytokine inhibitor — JTE-607 — Anti-inflammatory drug — Immunosuppression
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract. Objective and Design: We investigated the effect of a novel N-benzoyl-L-phenylalanine derivative compound (JTE-607) on production of various cytokines and other immune responses in vitro and on endotoxin shock in vivo.¶Materials and Methods: Human, monkey, rabbit, mouse and rat peripheral blood mononuclear cells (PBMCs), and human fibroblasts, umbilical vein endothelial cells (HUVEC), mesangial cells and T cells were used in vitro. Endotoxin shock was induced by lipopolysaccharide (LPS) in Corynebacterium parvum (C. parvum) sensitized male C57BL/6 mice in vivo.¶Results: JTE-607 inhibited inflammatory cytokine production, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8 and IL-10, from LPS-stimulated human PBMCs, with IC50 values of 11, 5.9, 8.8, 7.3 and 9.1 nM, respectively. The inhibitory effects of JTE-607 were also seen in mRNA expression of those cytokines. The potency of JTE-607 on cytokine production from PBMCs of other species, and from other human cells were much lower than that on human PBMCs. JTE-607 did not affect either LPS-stimulated microbead phagocytosis or reactive oxygen species production at 1 μM in human PBMCs but slightly suppressed expression of major histocompatibility complex class II antigen at 1 μM, although it was 100-fold less active than it was as a cytokine inhibitor. JTE-607 (0.3-10 mg/kg, i.v.) showed dose dependent inhibition of mortality after LPS challenge in C. parvum sensitized mice in accordance with a decrease of plasma TNF-α.¶Conclusions: These results suggest that JTE-607 is a multiple cytokine inhibitor specific for human PBMCs. This compound may be useful for the treatment of various cytokine mediated diseases such as septic shock without causing immunosuppression.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s000110050487
Permalink
