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NF-κB p65 and TCF-4 interactions are associated with LPS-stimulated IL-6 secretion of macrophages.

ABSTRACT: Proinflammatory cytokine plays a central role in host defense and acute inflammatory responses. Both positive and negative correlations of NF-κB and Wnt/β-catenin pathways have been reported depending on cell types in response to inflammatory stimuli for IL-6 cytokine production. Macrophages are vital to the regulation of immune responses and the development of inflammation, but the crosstalk between two pathways has not been elucidated so far in macrophages. We observed a positive cross-regulation between the NF-κB and Wnt/β-catenin pathways for IL-6 production in human macrophages. To verify the functional validity of this interaction, LY294002 or PNU74654, representative blockers of each pathway, were treated. IL-6 secretion was reduced to the basal level by both inhibitor treatments, even when stimulated by LPS. We also found that NF-κB p65 migrated to the nucleus and interacted with the transcription factor TCF-4 in macrophages upon LPS stimulation.

SUBMITTER: Kim JY

PROVIDER: S-EPMC10859262 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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NF-κB p65 and TCF-4 interactions are associated with LPS-stimulated IL-6 secretion of macrophages.

Kim Ji-Youn JY Jee Hyeon-Gun HG Kim Ju Yeong JY Yong Tai-Soon TS Jeon Soung-Hoo SH

Biochemistry and biophysics reports 20240206

Proinflammatory cytokine plays a central role in host defense and acute inflammatory responses. Both positive and negative correlations of NF-κB and Wnt/β-catenin pathways have been reported depending on cell types in response to inflammatory stimuli for IL-6 cytokine production. Macrophages are vital to the regulation of immune responses and the development of inflammation, but the crosstalk between two pathways has not been elucidated so far in macrophages. We observed a positive cross-regulat ...[more]

PMID: 38352245

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Project description:The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-κB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-κB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other anti-inflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-κB activation by the direct cleavage of NF-κB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-κB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.

Project description:Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

Dataset Information

NF-κB p65 and TCF-4 interactions are associated with LPS-stimulated IL-6 secretion of macrophages.

Publications

NF-κB p65 and TCF-4 interactions are associated with LPS-stimulated IL-6 secretion of macrophages.

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