Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.5.1.18 (
glutathione S-transferase
)
22,582
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Membrane-associated TNF-alpha cleavage is required to yield the 17.5-kD soluble product. This process is poorly understood in human cells, and no studies have related this process to the alveolar macrophage (AM). TNF-alpha-converting enzyme (TACE) is known to cleave TNF at the Ala-76-Val-77 site. We have evaluated the expression, regulation, and catalytic function of TACE in healthy human AMs. TACE was detected on the surface of AMs using flow cytometry. TACE protein can be upregulated by LPS (P = 0.036) and IFN-gamma. LPS-induced expression is downregulated by IL-10 (P = 0.04) and TNF-alpha. TACE regulation was observed at the mRNA level. TACE catalytic activity as assessed by cleavage of
glutathione S-transferase
-proTNF fusion protein correlates significantly with TACE protein expression (P = 0.04). However, cleavage and soluble TNF-alpha release by AMs was inhibited by matrix metalloproteinase and serine protease inhibitors, suggesting a role for a serine protease in this process. We confirmed the presence of
proteinase-3
(
PR-3
) on the AM surface that was functionally capable of TNF cleavage.
PR-3
mRNA expression was not found in AMs. However, we determined that
PR-3
from neutrophil supernatants could bind to the AM membrane, suggesting that AM-derived
PR-3
is from an exogenous source, which is important in the context of inflammation.
...
PMID:Contribution of TNF-alpha converting enzyme and proteinase-3 to TNF-alpha processing in human alveolar macrophages. 1621 Jun 95
Tumour necrosis factor (TNF) blockade has become an important immunomodulatory therapy, particularly in patients refractory to conventional immunosuppression, but responses can be unpredictable. Understanding the complex biology of TNF processing may be key to predicting such responses and reduce unwanted side effects. TNF bioavailability is regulated partly by TNF-alpha converting enzyme (TACE) cleavage; however, it can also be cleaved by
proteinase-3
(
PR-3
). We have demonstrated this mechanism previously in healthy human alveolar macrophages (AM), leading us to hypothesize that
PR-3
-mediated TNF processing may be an important mechanism in inflammatory lung disease. Furthermore, this may be more apparent in diseases with a neutrophil component typical of usual interstitial pneumonia (UIP), compared with sarcoidosis, where lymphocytes predominate. We isolated AM from patients with UIP and sarcoidosis and healthy subjects. We found increased TACE expression on AM in sarcoidosis. In contrast, TACE was not increased in UIP; we found increased cleavage of
glutathione S-transferase
-proTNF) substrate, relative to both sarcoidosis and healthy controls. Furthermore, cleavage was subject to inhibition by serine protease inhibitor, rather than a TACE inhibitor BB-3103. Cleavage was proportional to the number of neutrophils isolated from bronchoalveolar lavage, whereas there was an inverse relationship between neutrophils and BB-3103 inhibition. There was also increased
PR-3
on the AM surface in UIP relative to healthy controls. These data provide evidence for
PR-3
-mediated cleavage in UIP, which may have implications for future therapeutic targeting of TACE.
...
PMID:Tumour necrosis factor-alpha processing in interstitial lung disease: a potential role for exogenous proteinase-3. 1929 64
