Tumour necrosis factor-alpha processing in interstitial lung disease: a potential role for exogenous proteinase-3.
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.
Armstrong
L
L
University of Bristol, Department of Clinical Science North Bristol, Bristol, UK.
Godinho
S I H
SI
Uppington
K M
KM
Whittington
H A
HA
Millar
A B
AB
D051722:ADAM Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015153:Blotting, Western / Q000379:methods; D018893:Bronchoalveolar Lavage; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D017563:Lung Diseases, Interstitial / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D017565:Sarcoidosis, Pulmonary / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C108282:BB 3103; D006877:Hydroxamic Acids; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D005982:Glutathione Transferase; D053146:Myeloblastin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human