Ectodomain Shedding of Preadipocyte Factor 1 (Pref-1) by Tumor Necrosis Factor Alpha Converting Enzyme (TACE) and Inhibition of Adipocyte Differentiation

ABSTRACT Preadipocyte factor 1 (Pref-1), an epidermal growth factor repeat containing transmembrane protein found in the preadipocytes, inhibits adipocyte differentiation in vitro and in vivo. Here, we examined the processing of membrane form of Pref-1A to release the 50-kDa soluble form that inhibits adipocyte differentiation. The ectodomain cleavage of Pref-1 is markedly enhanced by phorbol 12-myristate 13-acetate in a dose- and time-dependent manner. The basal and stimulated cleavage is inhibited by the broad metalloproteinase inhibitor GM6001, a fact that suggests that cleavage of membrane Pref-1A is dependent on a metalloproteinase. Next, we showed that release of soluble Pref-1A is inhibited by TAPI-0 and by a tissue inhibitor of metalloproteinase-3, TIMP-3, that can inhibit tumor necrosis factor alpha converting enzyme (TACE), but not by TIMP-1 or TIMP-2. On the other hand, overexpression of TACE increases Pref-1 cleavage to produce the 50-kDa soluble form. Furthermore, this cleavage was not detected in cells with TACE mutation or with TACE small interfering RNA. TACE-mediated shedding of Pref-1 ectodomain inhibits adipocyte differentiation of 3T3-L1 cells and in Pref-1-null mouse embryo fibroblasts transduced with Pref-1A. Identification of TACE as the major protease responsible for conversion of membrane-bound Pref-1 to the biologically active diffusible form provides a new insight into Pref-1 function in adipocyte differentiation.

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Sitafloxacin reduces tumor necrosis factor alpha (TNFα) converting enzyme (TACE) phosphorylation and activity to inhibit TNFα release from lipopolysaccharide-stimulated THP-1 cells

Scientific Reports ◽

10.1038/s41598-021-03511-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ippei Sakamaki ◽

Michika Fukushi ◽

Wakana Ohashi ◽

Yukie Tanaka ◽

Kazuhiro Itoh ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Systemic Reaction ◽

Dependent Manner ◽

Converting Enzyme ◽

Necrosis Factor Alpha ◽

Quinolone Antibiotics ◽

Factor Alpha ◽

Necrosis Factor

AbstractSepsis is a systemic reaction to an infection and resulting in excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study aimed to identify quinolone antibiotics that can reduce tumor necrosis factor alpha (TNFα) production and to elucidate mechanisms underlying inhibition of TNFα production. We identified quinolone antibiotics reduced TNFα production in lipopolysaccharide (LPS)-stimulated THP-1 cells. Sitafloxacin (STFX) is a broad-spectrum antibiotic of the quinolone class. STFX effectively suppressed TNFα production in LPS-stimulated THP-1 cells in a dose-dependent manner and increased extracellular signal-regulated kinase (ERK) phosphorylation. The percentage of intracellular TNFα increased in LPS-stimulated cells with STFX compared with that in LPS-stimulated cells. TNFα converting enzyme (TACE) released TNFα from the cells, and STFX suppressed TACE phosphorylation and activity. To conclude, one of the mechanisms underlying inhibition of TNFα production in LPS-stimulated THP-1 cells treated with STFX is the inhibition of TNFα release from cells via the suppression of TACE phosphorylation and activity. STFX may kill bacteria and suppress inflammation. Therefore, it can be effective for sepsis treatment.

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Tumor Necrosis Factor Alpha Converting Enzyme (TACE) as Possible Therapeutic Target in SARS-CoV-2 Induced Acute Respiratory Distress Syndrome (ARDS)

10.26434/chemrxiv.13174415.v1 ◽

2020 ◽

Author(s):

Joao Batista Junior

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Inflammatory Responses ◽

Converting Enzyme ◽

Necrosis Factor Alpha ◽

Tace Inhibitors ◽

Factor Alpha ◽

Activity State ◽

Necrosis Factor

<div>This study reveals, for the first time, that rosiglitazone and pioglitazone, two thiazolidinedione drugs already approved as therapeutic agents to treat type II diabetes, were found to bind favorably to tumor necrosis factor alpha converting enzyme catalytic site with highlighted binding features.</div><div><br></div>This study suggests that rosiglitazone and pioglitazone, acting as TACE inhibitors agents might avoid or attenuate the hyperexcitability proteolytic activity state of TACE, represent a new potential therapeutic approach to treat SARS-CoV-2 infection-associated severe systemic inflammatory responses observed among severely or critically ill SARS-CoV-2 patients and, consequently, to diminish severe inflammatory‐induced lung injury, ARDS development and death rates.<br><br>

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Faculty Opinions recommendation of Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1026674.323460 ◽

2005 ◽

Author(s):

Judith White

Keyword(s):

Breast Cancer ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Converting Enzyme ◽

Cancer Marker ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

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Structure and functions of tumor necrosis factor-alpha converting enzyme.

Acta Biochimica Polonica ◽

10.18388/abp.2003_3656 ◽

2003 ◽

Vol 50 (3) ◽

pp. 625-645 ◽

Cited By ~ 45

Author(s):

Renata Mezyk ◽

Monika Bzowska ◽

Joanna Bereta

Keyword(s):

Tumor Necrosis Factor ◽

Substrate Specificity ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Converting Enzyme ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Structure And Functions ◽

Necrosis Factor

Tumor necrosis factor-alpha converting enzyme (TACE) is the first described and best characterized secretase. In this review the structure and the possible roles for TACE are summarized. The substrate specificity and the regulation of TACE activity as well as redundancy and possible cooperations of distinct secretases are also discussed.

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Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.11.6.1140-1147.2004 ◽

2004 ◽

Vol 11 (6) ◽

pp. 1140-1147 ◽

Cited By ~ 17

Author(s):

Hidenori Matsuzaki ◽

Hiroshi Kobayashi ◽

Tatsuo Yagyu ◽

Kiyoshi Wakahara ◽

Toshiharu Kondo ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Factor Alpha ◽

Dose Dependent ◽

Necrosis Factor

ABSTRACT Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-α) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-α expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-α protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 μM). (iii) Inhibition by bikunin of TNF-α induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-α target molecules interleukin-1β (IL-1β) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-α release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-α production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

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