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Published ahead of print on September 7, 2006, doi:10.1164/rccm.200605-632OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 11, December 2006, 1189-1198

A more recent version of this article appeared on December 1, 2006
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Submitted on May 9, 2006
Accepted on September 6, 2006

Inflammatory Lung Secretions Inhibit Dendritic Cell Maturation and Function via Neutrophil Elastase

Ali Roghanian1, Ellen M Drost2, William MacNee2, Sarah E.M. Howie3, and Jean-Michel Sallenave4*

1 Lung Inflammation Group, Edinburgh University Medical School, The Queen's Medical Research Institute, MRC Centre for Inflammation Research, Edinburgh, Scotland, United Kingdom; Immunobiology Group, Edinburgh University Medical School, The Queen's Medical Research Institute, MRC Centre for Inflammation Research, Edinburgh, Scotland, United Kingdom, 2 ELEGI/Colt Laboratories, Edinburgh University Medical School, The Queen's Medical Research Institute, MRC Centre for Inflammation Research, Edinburgh, Scotland, United Kingdom, 3 Immunobiology Group, Edinburgh University Medical School, The Queen's Medical Research Institute, MRC Centre for Inflammation Research, Edinburgh, Scotland, United Kingdom, 4 Lung Inflammation Group, Edinburgh University Medical School, The Queen's Medical Research Institute, MRC Centre for Inflammation Research, Edinburgh, Scotland, United Kingdom

* To whom correspondence should be addressed. E-mail: J.Sallenave{at}ed.ac.uk.

Rationale: Continuous episodes of infection are a feature of lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Since lung antigen presenting dendritic cells (DCs) sample inhaled antigen to initiate immune responses, 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 COPD and CF patients or NE can alter DC phenotype and function. Method: NE and sputum samples were incubated with immature (i) or mature (m) murine DCs. DC phenotype and function were studied by assessing their expression of co-stimulatory molecules by FACS and Western Blot analysis and their ability to induce T cell proliferation. Results: COPD/CF sputum samples and human NE down-regulated the expression of CD40, CD80, CD86 (but not MHCII) on DCs and inhibited LPS-induced DC maturation. This effect was partially (sputa)/significantly (NE) reversed by addition of recombinant secretory leukocyte protease inhibitor (SLPI). 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 COPD/CF patients may disable DC 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.
Key words: Chronic obstructive pulmonary diseases; cystic fibrosis; neutrophil elastase; dendritic cells; co-stimulatory molecules




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