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Inflammatory lung secretions inhibit dendritic cell maturation and function via neutrophil elastase

Inflammatory lung secretions inhibit dendritic cell maturation and function via neutrophil elastase
Inflammatory lung secretions inhibit dendritic cell maturation and function via neutrophil elastase
Rationale: Continuous episodes of infection are a feature of lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Lung antigen-presenting dendritic cells (DCs) sample inhaled antigen to initiate immune responses. Therefore, we hypothesized that inflammatory mediators, such as neutrophil elastase (NE) released into the lung, may be able to modulate their activity.

Objective: To determine whether sputum (from patients with COPD and those with CF) or NE can alter DC phenotype and function.

Method: NE and sputum samples were incubated with immature or mature murine DCs (mDCs). DC phenotype and function were studied by fluorescence-activated cell sorter and Western Blot analysis, assessing their expression of costimulatory molecules and their ability to induce T cell proliferation.

Results: COPD/CF sputum samples and human NE downregulated the expression of CD40, CD80, and CD86 (but not major histocompatibility complex II) on DCs and inhibited LPS-induced DC maturation. This effect was partially (sputa) to significantly (NE) reversed by addition of recombinant secretory leukocyte protease inhibitor. Western Blot analysis showed that purified NE degraded CD86 in mDC lysates in a time- and dose-dependent fashion, and caused shedding of CD86 into the supernatants of mDC cultures. NE treatment also inhibited the antigen-presenting ability of mDCs, as measured by their ability to induce ovalbumin-specific D011.10-transgenic T-cell proliferation.

Conclusions: Our data indicate that NE in lung inflammatory secretions of patients with COPD/CF may disable DCs and prevent them from mounting an adequate immune response. This may have implications for the infection-driven generation of disease exacerbations in these two pathologies.
chronic obstructive pulmonary diseases, costimulatory molecules, cystic fibrosis, dendritic cells, neutrophil elastase
1073-449X
1189-98
Roghanian, Ali
e2b032c2-60a0-4522-a3d8-56a768792f36
Drost, Ellen M.
ef6b1eb0-89bc-459e-aef7-9e6a6f465a5c
MacNee, William
5a5b8409-d0d4-4f2c-a2cb-18530b5f7351
Howie, Sarah E.M.
e2cf70f8-ec30-4b56-b845-65994078c704
Sallenave, Jean-Michel
dbe1dd6a-e3df-48dc-946c-d874b140460f
Roghanian, Ali
e2b032c2-60a0-4522-a3d8-56a768792f36
Drost, Ellen M.
ef6b1eb0-89bc-459e-aef7-9e6a6f465a5c
MacNee, William
5a5b8409-d0d4-4f2c-a2cb-18530b5f7351
Howie, Sarah E.M.
e2cf70f8-ec30-4b56-b845-65994078c704
Sallenave, Jean-Michel
dbe1dd6a-e3df-48dc-946c-d874b140460f

Roghanian, Ali, Drost, Ellen M., MacNee, William, Howie, Sarah E.M. and Sallenave, Jean-Michel (2006) Inflammatory lung secretions inhibit dendritic cell maturation and function via neutrophil elastase. American Journal of Respiratory and Critical Care Medicine, 174 (11), 1189-98. (doi:10.1164/rccm.200605-632OC). (PMID:16959917)

Record type: Article

Abstract

Rationale: Continuous episodes of infection are a feature of lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Lung antigen-presenting dendritic cells (DCs) sample inhaled antigen to initiate immune responses. Therefore, we hypothesized that inflammatory mediators, such as neutrophil elastase (NE) released into the lung, may be able to modulate their activity.

Objective: To determine whether sputum (from patients with COPD and those with CF) or NE can alter DC phenotype and function.

Method: NE and sputum samples were incubated with immature or mature murine DCs (mDCs). DC phenotype and function were studied by fluorescence-activated cell sorter and Western Blot analysis, assessing their expression of costimulatory molecules and their ability to induce T cell proliferation.

Results: COPD/CF sputum samples and human NE downregulated the expression of CD40, CD80, and CD86 (but not major histocompatibility complex II) on DCs and inhibited LPS-induced DC maturation. This effect was partially (sputa) to significantly (NE) reversed by addition of recombinant secretory leukocyte protease inhibitor. Western Blot analysis showed that purified NE degraded CD86 in mDC lysates in a time- and dose-dependent fashion, and caused shedding of CD86 into the supernatants of mDC cultures. NE treatment also inhibited the antigen-presenting ability of mDCs, as measured by their ability to induce ovalbumin-specific D011.10-transgenic T-cell proliferation.

Conclusions: Our data indicate that NE in lung inflammatory secretions of patients with COPD/CF may disable DCs and prevent them from mounting an adequate immune response. This may have implications for the infection-driven generation of disease exacerbations in these two pathologies.

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More information

e-pub ahead of print date: 7 September 2006
Published date: 1 December 2006
Keywords: chronic obstructive pulmonary diseases, costimulatory molecules, cystic fibrosis, dendritic cells, neutrophil elastase
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 369618
URI: http://eprints.soton.ac.uk/id/eprint/369618
ISSN: 1073-449X
PURE UUID: b23d0f5f-b904-4f47-a19b-0e1625a18faa
ORCID for Ali Roghanian: ORCID iD orcid.org/0000-0003-1316-4218

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Date deposited: 02 Oct 2014 09:15
Last modified: 15 Mar 2024 03:34

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Contributors

Author: Ali Roghanian ORCID iD
Author: Ellen M. Drost
Author: William MacNee
Author: Sarah E.M. Howie
Author: Jean-Michel Sallenave

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