Proteasome inhibition induces TNFR1 shedding from human airway epithelial (NCI-H292) cells
Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bldg. 10, Rm. 6D03, MSC 1590, Bethesda, MD 20892-1590, USA. AJP Lung Cellular and Molecular Physiology
(Impact Factor: 4.08).
09/2005; 289(2):L233-43. DOI: 10.1152/ajplung.00469.2004
The type 1 55-kDa TNF receptor (TNFR1) is an important modulator of lung inflammation. Here, we hypothesized that the proteasome might regulate TNFR1 shedding from human airway epithelial cells. Treatment of NCI-H292 human airway epithelial cells for 2 h with the specific proteasome inhibitor clasto-lactacystin beta-lactone induced the shedding of proteolytically cleaved TNFR1 ectodomains. Clasto-lactacystin beta-lactone also induced soluble TNFR1 (sTNFR1) release from the A549 pulmonary epithelial cell line, as well as from primary cultures of human small airway epithelial cells and human umbilical vein endothelial cells. Furthermore, sTNFR1 release induced by clasto-lactacystin beta-lactone was not a consequence of apoptosis or the extracellular release of TNFR1 exosome-like vesicles. The clasto-lactacystin beta-lactone-induced increase in TNFR1 shedding was associated with reductions in cell surface receptors and intracytoplasmic TNFR1 stores that were primarily localized to vesicular structures. As expected, the broad-spectrum zinc metalloprotease inhibitor TNF-alpha protease inhibitor 2 (TAPI-2) attenuated clasto-lactacystin beta-lactone-mediated TNFR1 shedding, which is consistent with its ability to inhibit the zinc metalloprotease-catalyzed cleavage of TNFR1 ectodomains. TAPI-2 also reduced TNFR1 on the cell surface and attenuated the clasto-lactacystin beta-lactone-induced reduction of intracytoplasmic TNFR1 vesicles. This suggests that TNFR1 shedding induced by clasto-lactacystin beta-lactone involves the zinc metalloprotease-dependent trafficking of intracytoplasmic TNFR1 vesicles to the cell surface. Together, these data are consistent with the conclusion that proteasomal activity negatively regulates TNFR1 shedding from human airway epithelial cells, thus identifying previously unrecognized roles for the proteasome and zinc metalloproteases in modulating the generation of sTNFRs.
Available from: Michael F McDermott
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ABSTRACT: The tumour necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) is an autosomal dominant, multisystemic, autoinflammatory disorder caused by mutations in the TNFR1 gene ( TNFRSF1A ). Traps seems to be the most common hereditary periodic fever (HPF) syndrome in some western populations, and the second most prevalent HPF worldwide, behind familial mediterranean fever (FMF). The proteins involved in susceptibility to TRAPS (TNFRSF1A) and FMF (pyrin) are both members of the death-domain-fold superfamily. Mutations affecting these proteins might cause dysregulation of innate immune responses, with a propensity to autoinflammation. Most TRAPS patients have reduced blood levels of soluble TNFRSF1A between attacks, with an inappropriately small increase during bouts of fever. The pathogenesis of the 'hyperinflammatory state' in TRAPS has been variously ascribed to a shedding defect of TNFRSF1A from the cell surface resulting in increased TNF inflammatory signalling, or impaired TNF apoptotic signalling. Some low-penetrance TNFRSF1A variants also contribute to the clinical phenotype in individuals carrying other HPF-associated mutations, and have been reported in several disorders such as Behçet's disease and systemic lupus erythematosus. Synthetic anti-TNF agents provide a rational form of therapy for TRAPS, and have been shown to delay or indeed prevent development of systemic amyloidosis (AA type), a life-threatening complication in this condition.
Expert Reviews in Molecular Medicine 11/2005; 7(22):1-18. DOI:10.1017/S1462399405009749 · 5.15 Impact Factor
Available from: Toyoko Hiroi
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ABSTRACT: The type I, 55-kDa tumor necrosis factor receptor (TNFR1) is released from cells to the extracellular space where it can bind and modulate TNF bioactivity. Extracellular TNFR1 release occurs by two distinct pathways: the inducible proteolytic cleavage of TNFR1 ectodomains and the constitutive release of full-length TNFR1 in exosome-like vesicles. Regulation of both TNFR1 release pathways appears to involve the trafficking of cytoplasmic TNFR1 vesicles. Vesicular trafficking is controlled by ADP-ribosylation factors (ARFs), which are active in the GTP-bound state and inactive when bound to GDP. ARF activation is enhanced by guanine nucleotide-exchange factors that catalyze replacement of GDP by GTP. We investigated whether the brefeldin A (BFA)-inhibited guanine nucleotide-exchange proteins, BIG1 and/or BIG2, are required for TNFR1 release from human umbilical vein endothelial cells. Effects of specific RNA interference (RNAi) showed that BIG2, but not BIG1, regulated the release of TNFR1 exosome-like vesicles, whereas neither BIG2 nor BIG1 was required for the IL-1beta-induced proteolytic cleavage of TNFR1 ectodomains. BIG2 co-localized with TNFR1 in diffusely distributed cytoplasmic vesicles, and the association between BIG2 and TNFR1 was disrupted by BFA. Consistent with the preferential activation of class I ARFs by BIG2, ARF1 and ARF3 participated in the extracellular release of TNFR1 exosome-like vesicles in a nonredundant and additive fashion. We conclude that the association between BIG2 and TNFR1 selectively regulates the extracellular release of TNFR1 exosome-like vesicles from human vascular endothelial cells via an ARF1- and ARF3-dependent mechanism.
Journal of Biological Chemistry 04/2007; 282(13):9591-9. DOI:10.1074/jbc.M607122200 · 4.57 Impact Factor
Available from: Atsushi Kato
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ABSTRACT: It has become increasingly clear that airway epithelial cells are central participants in innate and adaptive immune responses as well as mucosal inflammation. Epithelial cells produce antimicrobial host defense molecules, proinflammatory cytokines and chemokines in response to activation via pathogen recognition receptors. Recruitment of immune cells including dendritic cells, T cells and B cells into the proximity of epithelium results in the enhancement of adaptive immunity through interactions with epithelial cells. Newly identified epithelial-derived cytokines, including TSLP, IL-33 and BAFF, help to shape the local accumulation and activation of Th2 responses and B cell immunoglobulin production. Epithelial cells are also downstream targets of molecules that activate IL-13R and EGFR and are responsible for mucus production in both protective immune responses and allergic airway inflammatory diseases. Improved understanding of epithelial immune and inflammatory responses will hopefully suggest new strategies for therapeutic intervention.
Current Opinion in Immunology 01/2008; 19(6):711-20. DOI:10.1016/j.coi.2007.08.004 · 7.48 Impact Factor
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