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Published ahead of print on October 6, 2005, doi:10.1165/rcmb.2005-0087OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 2, February 2006, 219-225

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Submitted on March 1, 2005
Revised on September 26, 2005

Contribution of TACE and Proteinase-3 to TNF-{alpha} Processing in Human Alveolar Macrophages

Lynne Armstrong1, Sofia I.H. Godinho1, Kay M Uppington1, Hayley A Whittington1, and Ann B Millar1*

1 Department of Clinical Science at North Bristol, University of Bristol, Bristol, United Kingdom

* To whom correspondence should be addressed. E-mail: Ann.Millar{at}bristol.ac.uk.

Membrane-associated TNF-{alpha} (mTNF) cleavage is required to yield the 17.5 kDa soluble product (sTNF). This process is poorly understood in human cells and no studies have related 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 AM. TACE was detected on the surface of AM using flow cytometry. TACE protein can be upregulated by LPS (p=0.036) and IFN-{gamma}. LPS-induced expression is down regulated 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 GST-proTNF fusion protein correlates significantly with TACE protein expression (p = 0.04). However, cleavage and soluble TNF-{alpha} release by AM was inhibited by both MMP 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 AM. 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, of particular importance in the context of inflammation.




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