Tumour necrosis factor-alpha processing in interstitial lung disease: a potential role for exogenous proteinase-3

L Armstrong, SIH Godinho, KM Uppington, HA Whittington, AB Millar

Research output: Contribution to journalArticle (Academic Journal)peer-review

16 Citations (Scopus)

Abstract

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.
Translated title of the contributionTumour necrosis factor-alpha processing in interstitial lung disease: a potential role for exogenous proteinase-3
Original languageEnglish
Pages (from-to)336 - 343
Number of pages7
JournalClinical and Experimental Immunology
Volume156
DOIs
Publication statusPublished - Mar 2009

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