A novel dual regulator of tumor necrosis factor-α and interleukin-10 protects mice from endotoxin-induced shock

Immunotherapy for nonalcoholic steatohepatitis using themultiple cytokine production modulator Y-40138

“…has not yet been elucidated, it is known to have reciprocal actions in inhibiting production of TNF-α and IFN-γ, and increasing production of IL-10, as well as inhibiting production of chemokines and inflammatory cell chemotaxis, mechanisms not seen in any other agents [8,9] . Previous studies on Y-40138 have demonstrated improved survival rates in a D-galactosamine/LPS-induced mouse fulminant hepatic failure model [25,26] and a LPS-stimulated mouse sepsis model [27] , and reduced ALT levels in a concanavalin A-induced mouse hepatitis model [28] . In this study using the rat NASH model, we detected increased plasma levels of ALT and TNF-α, and confirmed increased TNF-α levels in the liver using ELISA and immunohistochemical staining.…”

Nuclear Factor-κB Blockade Attenuates but Does Not Abrogate Lipopolysaccharide-Dependent Tumor Necrosis Factor-α Biosynthesis in Alveolar Epithelial Cells

“…For instance, a novel recent study by Haskó et al (23) reported a potential role for extracellular purines, including adenosine and ATP, and inosine, a degradation product of these purines, as potent endogenous immunomodulatory molecules that inhibit inflammatory cytokine biosynthesis and protect against endotoxin-induced shock. It has also been reported, in addition, that selective inhibition of phosphodiesterases, a family of enzymes involved in the degradation of cAMP (24,25), steroids, such as glucocorticoids (26), pyrimidylpiperazine derivatives (19,(27)(28)(29), and ERK and p38/RK MAPK selective inhibitors (30,31) differentially regulate the transcription and biosynthesis of inflammatory cytokines. The promoters of genes encoding cytokines contain multiple cis-acting motifs including those that bind such transcription factors as NF-B.…”

Y-40138, a multiple cytokine production modulator, protects against d-galactosamine and lipopolysaccharide-induced hepatitis

“…Y-40138 is a small molecular synthetic compound that suppresses TNF-α production and augments IL-10 production in LPS-injected mice (Fukuda et al, 2000). In D-GalN/LPStreated mice, Y-40138 suppressed plasma ALT levels dosedependently and inhibited TNF-α levels.…”

“…In addition to its pivotal role in controlling the recruitment of inflammatory cells, increases in MCP-1 expression have been linked to the progression of experimental fungal pneumonia and autoimmune diseases including rheumatoid arthritis and multiple sclerosis (Gong et al, 1997;Huang et al, 2001). Y-40138, N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methylphenyl)cyclopropyl] acetamide HCl, has been reported to inhibit LPS-induced TNF-α production and augment IL-10 production in mice (Fukuda et al, 2000).…”