JTE-607, a novel inflammatory cytokine synthesis inhibitor without immunosuppression, protects from endotoxin shock in mice

Objective and Design: We investigated the effect of a novel N-benzoyl-L-phe nylalanine 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 Mood mononuclear cells (PBMCs), and human fibroblasts, umbilical vein endotheli al 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 tumo r necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-8 and IL-1 0, from LPS-stimulated human PBMCs, with IC50 values of Il, 5.9, 8.8, 7.3 a nd 9.1 nM, respectively. The inhibitory effects of JTE-607 were also seen i n mRNA expression of those cytokines. The potency of JTE-607 on cytokine pr oduction 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-stimulate d microbead phagocytosis or reactive oxygen species production at I mu M in human PBMCs but slightly suppressed expression of major histocompatibility complex class II antigen at 1 mu M, although it was 100-fold less active t han it was as a cytokine inhibitor. JTE-607 (0.3-10 mg/kg, i.v.) showed dos e dependent inhibition of mortality after LPS challenge in C. parvum sensit ized mice in accordance with a decrease of plasma TNF-alpha. Conclusions: These results suggest that JTE-607 is a multiple cytokine inhi bitor specific for human PBMCs. This compound may be useful for the treatme nt of various cytokine mediated diseases such as septic shock without causi ng immunosuppression.