Converting enzyme-independent release of tumor necrosis factor alpha and IL-1 beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3
C. Coeshott et al., Converting enzyme-independent release of tumor necrosis factor alpha and IL-1 beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3, P NAS US, 96(11), 1999, pp. 6261-6266
Citations number
49
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Two important cytokines mediating inflammation are tumor necrosis factor cu
(TNF alpha) and IL-1 beta, both of which require conversion to soluble for
ms by converting enzymes. The importance of TNF alpha-converting enzyme and
IL-lp-converting. enzyme in the production of circulating TNF alpha and IL
-1 beta in response to systemic challenges has been demonstrated by the use
of specific converting enzyme inhibitors. Many inflammatory responses, how
ever, are not systemic but instead are localized. In these situations relea
se and/or activation of cytokines may be different from that seen in respon
se to a systemic stimulus, particularly because associations of various cel
l populations in these foci allows for the exposure of procytokines to the
proteolytic enzymes produced by activated neutrophils, neutrophil elastase
(NE), proteinase 3 (PR3), and cathepsin G (Cat G), To investigate the possi
bility of alternative processing of TNF alpha and/or IL-1 beta by neutrophi
l-derived proteinases, immunoreactive TNF alpha and IL-1 beta release from
lipopolysaccharide-stimulated THP-1 cells was measured in the presence of a
ctivated human neutrophils. Under these conditions, TNFa and IL-1 beta rele
ase was augmented 2- to 5-fold. In the presence of a specific inhibitor of
NE and PR3, enhanced release of both cytokines was largely abolished; howev
er, in the presence of a NE and Cat G selective inhibitor, secretory leucoc
yte proteinase inhibitor, reduction of the enhanced release was minimal. Th
is finding suggested that the augmented release was attributable to PR3 but
not NE nor Cat G. Use of purified enzymes confirmed this conclusion. These
results indicate that there may be alternative pathways for the production
of these two proinflammatory cytokines, particularly in the context of loc
al inflammatory processes.