TNF‐α Induces Caspase‐1 Activation Independently of Simultaneously Induced NLRP3 in 3T3‐L1 Cells

Furuoka, Mana; Ozaki, Kei-ichi; Sadatomi, Daichi; Mamiya, Sayaka; Yonezawa, Tomo; Tanimura, Susumu; Takeda, Kohsuke

doi:10.1002/jcp.25385

Cited by 41 publications

(30 citation statements)

References 33 publications

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“…In support of our data, C. burnetii infection of primary macrophages does not activate caspase 1 (20), an enzyme required for the production of the proinflammatory cytokines IL-1␤ and IL-1␣ (55,56). Interestingly, C. burnetii does not directly inhibit caspase 1 activation but appears to interfere with upstream signaling events, including blocking TNF-␣ signaling (20,57). However, a recent study did not detect significant differences in TNF-␣ production in murine bone marrow-derived macrophages infected with WT C. burnetii or icmL mutant C. burnetii, a mutant with a nonfunctional T4BSS (31).…”

Section: Discussionsupporting

confidence: 77%

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

et al. 2018

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is an obligate intracellular bacterium and the etiological agent of Q fever. Successful host cell infection requires the type IVB secretion system (T4BSS), which translocates bacterial effector proteins across the vacuole membrane into the host cytoplasm, where they manipulate a variety of cell processes. To identify host cell targets of T4BSS effector proteins, we determined the transcriptome of murine alveolar macrophages infected with a T4BSS effector mutant. We identified a set of inflammatory genes that are significantly upregulated in T4BSS mutant-infected cells compared to mock-infected cells or cells infected with wild-type (WT) bacteria, suggesting that T4BSS effector proteins downregulate the expression of these genes. In addition, the interleukin-17 (IL-17) signaling pathway was identified as one of the top pathways affected by the bacteria. While previous studies demonstrated that IL-17 plays a protective role against several pathogens, the role of IL-17 during infection is unknown. We found that IL-17 kills intracellular in a dose-dependent manner, with the T4BSS mutant exhibiting significantly more sensitivity to IL-17 than WT bacteria. In addition, quantitative PCR confirmed the increased expression of IL-17 downstream signaling genes in T4BSS mutant-infected cells compared to WT- or mock-infected cells, including the proinflammatory cytokine genes ,, and , the chemokine genes and , and the antimicrobial protein gene We further confirmed that the T4BSS downregulates macrophage CXCL2/macrophage inflammatory protein 2 and CCL5/RANTES protein levels following IL-17 stimulation. Together, these data suggest that downregulates IL-17 signaling in a T4BSS-dependent manner in order to escape the macrophage immune response.

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Section: Discussionsupporting

confidence: 77%

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

et al. 2018

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“…The inflammatory response caused by the NLRP3 inflammasome is triggered in a variety of situations that pose a threat to the host, including TNF-α, the NF-κB pathway, and ROS [9,14,50,51]. In our previous work, we demonstrated that hydrogen treatment activates TNF-α and the NF-κB Fig.…”

Section: Discussionmentioning

confidence: 94%

Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway

et al. 2020

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Background: Pyroptosis belongs to a novel inflammatory programmed cell death pathway, with the possible prognosis of endometrial cancer related to the terminal protein GSDMD. Hydrogen exerts a biphasic effect on cancer by promoting tumor cell death and protecting normal cells, which might initiate GSDMD pathway-mediated pyroptosis. Methods: We performed immunohistochemical staining and western immunoblotting analysis to observe expression of NLRP3, caspase-1, and GSDMD in human and xenograft mice endometrial cancer tissue and cell lines. We investigated treatment with hydrogen could boost ROS accumulation in endometrial cancer cells by intracellular and mitochondrial sources. GSDMD shRNA lentivirus was used to transfect endometrial cancer cells to investigate the function of GSDMD protein in pyroptosis. Propidium iodide (PI) staining, TUNEL assay, measurement of lactate dehydrogenase (LDH) release and IL-1β ELISA were used to analysis pyroptosis between hydrogensupplemented or normal culture medium. We conducted in vivo human endometrial tumor xenograft mice model to observe anti-tumor effect in hydrogen supplementation. Results: We observed overexpression of NLRP3, caspase-1, and GSDMD in human endometrial cancer and cell lines by IHC and western immunoblotting. Hydrogen pretreatment upregulated ROS and the expression of pyroptosisrelated proteins, and increased the number of PI-and TUNEL-positive cells, as well as the release of LDH and IL-1β, however, GSDMD depletion reduced their release. We further demonstrated that hydrogen supplementation in mice was sufficient for the anti-tumor effect to inhibit xenograft volume and weight of endometrial tumors, as mice subjected to hydrogen-rich water displayed decreased radiance. Tumor tissue sections in the HRW groups presented moderate-to-strong positive expression of NLRP3, caspase-1 and GSDMD. Hydrogen attenuated tumor volume and weight in a xenograft mouse model though the pyroptotic pathway. Conclusions: This study extended our original analysis of the ability of hydrogen to stimulate NLRP3 inflammasome/GSDMD activation in pyroptosis and revealed possible mechanism (s) for improvement of antitumor effects in the clinical management of endometrial cancer.

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“…On the other hand, these cytokines act by stimulating the activation of NF-κB, maintaining a cycle of cellular activation [33]. Although not directly related to the inflammasomes, a recent study demonstrated that in vitro stimulation with TNF-α induces the early expression of NLRP3 mRNA in a 3T3-LI adipocyte line and it is detected after one hour of culture suggesting that NLRP3 gene expression is immediately responsive to TNF-α [34].…”

Section: Discussionmentioning

confidence: 99%

Induction of systemic inflammation by hyaluronan and hsp70 in women with pre-eclampsia

et al. 2018

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Pre-eclampsia (PE) is a human pregnancy syndrome with abnormal activation of the innate immune response. The study evaluated the involvement of molecular structures called damage-associated molecular patterns (DAMPs), such as hyaluronan (HA) and heat shock proteins (Hsp) on NLRP1 and NLRP3 inflammasomes activation in peripheral blood monocytes. Twenty pre-eclamptic women, 20 normotensive pregnant women (NT) and 20 non-pregnant women (NP) were studied. Enzyme immunoassay was employed for the determination of HA, Hsp70 and High mobility group Box 1 (HMGB1) in plasma, as well as for the detection of Interleukin-1β (IL-1β), IL-18 and tumor necrosis factor alpha (TNF-α) in the supernatant of monocytes cultured with or without HA and Hsp70. The inflammasomes induction was evaluated by the quantification of mRNA for NLRP1, NLRP3, caspase-1, IL-1β, IL-18, HMGB1 and TNF-α by qPCR in monocyte culture. The results showed significantly higher plasma levels of HA, Hsp70 and HMGB1 in pre-eclamptic women than in NT and NP women. Monocytes from women with PE showed endogenous activation of NLRP1 and NLRP3 inflammasomes, and expressed high amounts of IL-1β, IL-18, HMGB1 and TNF-α. The stimulation of monocytes with HA increased the gene expression of NLRP1, NLRP3, caspase-1, TNF-α, IL-1β, HMGB1 and IL-18 and the production of IL-1β in pre-eclamptic women. Monocytes cultured with Hsp70 produced elevated levels of IL-1β and TNF-α through a mechanism independent of inflammasomes activation. These results suggest the participation of these DAMPs in the systemic inflammatory response that is characteristic of PE.

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TNF‐α Induces Caspase‐1 Activation Independently of Simultaneously Induced NLRP3 in 3T3‐L1 Cells

Cited by 41 publications

References 33 publications

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway

Induction of systemic inflammation by hyaluronan and hsp70 in women with pre-eclampsia

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