IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.

Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/ HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

IB kinase (IKK) ␤ is essential for inflammatory cytokine-induced activation of nuclear factor B (NF-B). NF-B plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKK␤ inhibitor N- (6-chloro-7-methoxy-9H-␤-carbolin-8-yl)-2-methylnicotinamide (ML120B), a ␤-carboline derivative, on NF-B signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKK␤ with an IC 50 of 60 nM when evaluated in an IB␣ kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentrationdependently inhibits tumor necrosis factor ␣ (TNF␣)-stimulated NF-B signaling via inhibition of IB␣ phosphorylation, degradation, and NF-B translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNF␣-or interleukin (IL)-1␤-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKK␤-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide-or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKK␤-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1␤-induced matrix metalloproteinase production with an IC 50 of approximately 1 M. ML120B also blocked IL-1␤-induced prostaglandin E 2 production. In summary, ML120B blocked numerous NF-B-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKK␤ inhibitors as anti-inflammatory agents for the treatment of RA.

The transcription factor NF-B plays a central role in regulating inflammation and apoptosis, making it a compelling target for drug development. We identified a small molecule inhibitor (ML120B) that specifically inhibits IKK␤, an Ikappa IntroductionNF-B plays a central role in inflammation and apoptosis, making it a primary target for inhibition for treatment of inflammatory disease and cancer. 1,2 NF-B consists of subunits that associate in dimers. 3,4 The commonly described dimer forms are p50 (NF-B1) with RelA (p65) and p52 (NF-B2) with RelB. IB␣ holds the p50/RelA complex in the cytoplasm in an inactive form. NF-B nuclear translocation is regulated by upstream signaling events initiated primarily by proinflammatory stimuli, resulting in activation of IKK. 5 IKK contains 3 related subunits: ␣, ␤, and ␥. IKK␤ is the subunit responsible for phosphorylating IB␣, resulting in its ubiquitination and subsequent proteasomal degradation. [6][7][8] Released NF-B translocates to the nucleus to initiate transcription of response genes, which include proinflammatory and antiapoptotic genes. 9 In addition to phosphorylating IB␣, IKK␤ also phosphorylates the transcription factor FOXO3a, which is also degraded by the proteasome. 10 FOXO3a that is not phosphorylated by IKK␤ can translocate to the nucleus where it upregulates expression of genes that control cell cycle progression [11][12][13] and induce apoptosis. 14,15 NF-B activation has been associated with several human immune modulated diseases including arthritis, asthma, diabetes, stroke, inflammatory bowel disease, and atherosclerosis. 16 In addition, IKK␤ and NF-B have been shown to play a direct role in regulating the development of insulin resistance 17,18 and in severe muscle wasting. 19 Recently, it has been demonstrated that IKK␤ and NF-B play a key role in inflammation-associated cancer and tumor progression. [20][21][22][23][24] These data suggest that inhibition of IKK␤ in vivo with a specific small molecule may be a potential therapeutic approach for several human diseases.In addition to controlling inflammatory response and apoptosis, IKK␤ and NF-B are required for normal lymphocyte development. Mice deficient in the p65 (RelA) subunit of NF-B or IKK␤ die during fetal development through a TNF-dependent mechanism. 6,25,26 Generation of p65-or IKK␤-deficient mice on a TNF␣-or TNFR-deficient background rescues mice from embryonic lethality. [27][28][29] Studies evaluating the requirement for NF-B in hematopoiesis using transplantation of fetal liver stem cells from p65-or IKK␤-deficient mice into lethally irradiated hosts have revealed a specific requirement for these molecules in development of T cells, B cells, and common lymphoid progenitors but not myeloid cells or stem cells and a role in regulating the production of granulocytes. [30][31][32] We identified ML120B, a specific small chemical inhibitor of IKK␤ that protects against cartilage and bone destruction in adjuvant and collagen-induced models of arthritis. 33 Here we demonstrate that IKK␤ inhib...

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Use of smaller-sized ETT combined with i.v. lidocaine decreases the incidence and severity of POST in women undergoing thyroid surgery.

Rip2 (Rick, Cardiak, CCK2, and CARD3) is a serine/ threonine kinase containing a caspase recruitment domain (CARD) at the C terminus. Previous reports have shown that Rip2 is involved in multiple receptor signaling pathways that are important for innate and adaptive immune responses. However, it is not known whether Rip2 kinase activity is required for its function. Here we confirm that Rip2 participates in lipopolysaccharide (LPS)/Toll-like receptor (TLR4) signaling and demonstrate that its kinase activity is not required. Upon LPS stimulation, Rip2 was transiently recruited to the TLR4 receptor complex and associated with key TLR signaling mediators IRAK1 and TRAF6. Furthermore, Rip2 kinase activity was induced by LPS treatment. These data indicate that Rip2 is directly involved in the LPS/ TLR4 signaling. Whereas macrophages from Rip2-deficient mice showed impaired NF-B and p38 mitogenactivated protein kinase activation and reduced cytokine production in response to LPS stimulation, LPS signaling was intact in macrophages from mice that express Rip2 kinase-dead mutant. These results demonstrate that Rip2-mediated LPS signaling is independent of its kinase activity. Our findings strongly suggest that Rip2 functions as an adaptor molecule in transducing signals from immune receptors.

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