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-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)-alpha, interleukin (IL)-1beta, 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 microM in human PBMCs but slightly suppressed expression of major histocompatibility complex class II antigen at 1 microM, 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-alpha.

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.