1The intracellular cysteine protease caspase-1 is critically involved in obesity-induced inflammation 2 in adipose tissue. A substantial body of evidence from immune cells, such as macrophages, has 3shown that caspase-1 activation depends largely on a protein complex, called the NLRP3 4 inflammasome, which consists of the NOD-like receptor (NLR) family protein NLRP3, the adaptor 5 protein ASC, and caspase-1 itself. However, it is not fully understood how caspase-1 activation is 6 regulated within adipocytes upon inflammatory stimuli. In this study, we show that TNF-α-induced 7 activation of caspase-1 is accompanied by robust induction of NLRP3 in 3T3-L1 adipocytes but that 8 caspase-1 activation may not depend on the NLRP3 inflammasome. Treatment of 3T3-L1 cells with 9 TNF-α induced mRNA expression and activation of caspase-1. Although the basal expression of 10 NLRP3 and ASC was undetectable in unstimulated cells, TNF-α strongly induced NLRP3 11 expression but did not induce ASC expression. Interestingly, inhibitors of the ERK MAP kinase 12 pathway strongly suppressed NLRP3 expression but did not suppress the expression and activation 13 of caspase-1 induced by TNF-α, suggesting that NLRP3 is dispensable for TNF-α-induced 14 caspase-1 activation. Moreover, we did not detect the basal and TNF-α-induced expression of other 15 NLR proteins (NLRP1a, NLRP1b, and NLRC4), which do not necessarily require ASC for 16 caspase-1 activation. These results suggest that TNF-α induces caspase-1 activation in an 17 inflammasome-independent manner in 3T3-L1 cells and that the ERK-dependent expression of 18
The NLRP3 inflammasome plays a critical role in the processing and release of inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. Accumulating evidence suggests that mitochondria are common mediators of NLRP3 inflammasome activation induced by a wide range of inflammatory stimuli; however, the precise role of mitochondria is still not fully understood. Here, we show that mitochondrial function is required for extracellular ATP-induced NLRP3 inflammasome activation. Extracellular ATP induced the loss of mitochondrial membrane potential and mitochondrial fragmentation in a different manner than other stimuli in primary mouse macrophages. CCCP, an uncoupler and antimycin A, an inhibitor of the mitochondrial electron transport chain, inhibited IL-1β release induced by ATP but not by other stimuli. CCCP did not inhibit the ATP-induced generation of reactive oxygen species and cell death, both of which are known to promote IL-1β release, but did inhibit the ATP-induced activation of caspase-1, a component of the NLRP3 inflammasome. These results suggest that mitochondrial function is required somewhat specifically for ATP-induced NLRP3 inflammasome activation. In contrast to many previous reports that dysfunctional mitochondria promote NLRP3 inflammasome activation, the function of intact mitochondria appears to be required for NLRP3 inflammasome activation, depending on the stimulus.
It has generally been considered that protein phosphatases have more diverse catalytic domain structures and mechanisms than protein kinases; however, gene annotation efforts following the human genome project appeared to have completed the whole array of protein phosphatases. Ser/Thr phosphatases are divided into three subfamilies that have different structures from each other, whereas Tyr phosphatases and dual-specificity phosphatases targeting Tyr, Ser and Thr belong to a single large family based on their common structural features. Several years of research have revealed, however, the existence of unexpected proteins, designated here as “atypical protein phosphatases”, that have structural and enzymatic features different from those of the known protein phosphatases and are involved in important biological processes. In this review, we focus on the identification and functional characterization of atypical protein phosphatases, represented by eyes absent (EYA), suppressor of T-cell receptor signaling (Sts) and phosphoglycerate mutase family member 5 (PGAM5) and discuss their biological significance in cellular signaling.
TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.