CEP-11004, an inhibitor of the SAPK/JNK pathway, reduces TNF-α release from lipopolysaccharide-treated cells and mice

Abstract

CEP 11004, a mixed lineage kinase (MLK) inhibitor, was examined for its effects on tumor necrosis factor alpha (TNF a) production in human THP 1 monocytes, mouse BV 2 microglia, and C57Bl/6 mice. CEP 11004 inhibited TNF a secretion up to 90% in THP 1 cells incubated with 3 Ag/ml lipopolysaccharide, with an IC 50 of 137 T 14 nM. CEP 11004 also inhibited TNF a production in lipopolysaccharide stimulated microglial cells, but did not inhibit the initial increase in TNF a mRNA expression as measured by real time polymerase chain reaction (PCR). The mitogen activated protein kinases (MAPKs) phospho c jun N terminal kinase (JNK), phospho p38, and phospho MAPK kinase 4 (MKK4) levels were increased in THP 1 cells following lipopolysaccharide treatment, and were reduced by CEP 11004 treatment. For in vivo studies, CEP 11004 was injected 2 h prior to lipopolysaccharide (20 mg/kg) administration. CEP 11004 significantly inhibited TNF a production at doses of 1 10 mg/kg as measured by enzyme linked immunosorbent assay (ELISA). These results suggest that MLK blockade may be useful in inhibiting pro inflammatory cytokine production in a wide range of diseases. D

Inhibition of Mixed Lineage Kinase 3 Prevents HIV-1 Tat-Mediated Neurotoxicity and Monocyte Activation

“…These findings extend previous reports that CEP1347 can reduce the production of proinflammatory cytokines (TNF-␣, IL-6) and chemokines (MCP-1) by primary human and rat microglia after exposure to bacterial endotoxins or to the Alzheimer's peptide, A␤ (65), as well as similar findings that were obtained using CEP11004 (66). Overall, this suggests that CEP1347 might have the desirable effect of reducing the activation of cells of myeloid lineage within the CNS (and periphery) of persons with HAD, thereby reducing monocyte recruitment into the CNS and also inhibiting the local generation of neurotoxic effector molecules within the CNS.…”

RETRACTED: GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38

“…2A). The indolocarbazole analogue CEP-11004 is a potent and specific inhibitor of MLK family kinases-especially MLK3, in vitro and in vivo (36,37). Treatment of gckϩ/ϩ BMMs with CEP11004 substantially impairs LPS activation of JNK and p38 but is without effect on ERK activation (Fig.…”

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

“…Mitogen-activated protein kinases (MAPKs), the predominant signaling transduction pathway responsible for synthesis and production of proinflammatory factors in microglia, can be regulated by mitochondrial function (Akundi et al, 2005;Ciallella et al, 2005;Lund et al, 2005;Waetzig et al, 2005). In the present study, microglia were treated with rotenone (10 nM) for different intervals of time to determine the involvement of MAPK after rotenone stimulation.…”

“…However, the exact mechanism underlying the inhibition of microglial activation by opening mitoK ATP channels remains unknown. Mitochondrial membrane potential and the downstream MAPKs have been demonstrated to regulate microglial activation and the production of proinflammatory factors from microglia (Akundi et al, 2005;Ciallella et al, 2005;Lund et al, 2005;Waetzig et al, 2005). The inhibitory effects of IPT on rotenone-induced DC m loss and p38/JNK MAPK activation were abolished by addition of 5-HD, indicating IPT might regulate mitochondrial function and MAPKs pathways through opening mitoK ATP channels.…”