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Human lung fibroblasts secrete nerve growth factor: effect of inflammatory cytokines and glucocorticoids

¹ Institut National de la Santé et de la Recherche Médicale (INSERM) U425, Neuroimmunopharmacologie Pulmonaire, Faculté de Pharmacie, Université Louis Pasteur Strasbourg I, Illkirch Cedex, France. ² Dept of Medicine, Division of Respiratory Medicine, Karolinska Hospital, 17176, Stockholm, Sweden

CORRESPONDENCE: N. Frossard, INSERM U425, Neuroimmunopharmacologie Pulmonaire, Faculté de Pharmacie, Université Louis Pasteur Strasbourg I, B.P. 24, 67 401, Illkirch Cedex, France. Fax: 33 390244309

Keywords: airway, glucocorticoid, inflammation, interleukin-1ß, nerve growth factor

Received: August 8, 2000
Accepted January 25, 2001

The project was funded by INSERM. C. Olgart was supported by the Swedish MRC, T. and R. Söderberg's Foundations, E. and E. Fernström's Foundation, and Comité Départemental du Bas-Rhin Contre les Maladies Respiratoires et la Tuberculose, UCB Institute of Allergy, Brussels, Belgium.

Nerve growth factor (NGF) has recently been suggested to contribute to inflammation and bronchial hyperresponsiveness in asthma. However, the cell types capable of NGF production in the human lung and airways, as well as the regulatory role of pro-inflammatory cytokines and of glucocorticoids on NGF secretion in pulmonary cells, have not been described.

Human pulmonary fibroblasts were cultured in the presence or absence of either interleukin-1ß (IL-1ß), tumour necrosis factor- (TNF-) and/or glucocorticoids. NGF secretion was measured by enzyme-linked immunosorbent assay.

The human pulmonary fibroblasts constitutively secreted NGF in vitro. The rate of NGF secretion was shown to be cell density-dependent, since higher NGF secretion was detected in preconfluent cells, i.e. ones with less established cell-to-cell contact (41.0±5.0 pg·10^–6 cells at 80% confluence), than cells in higher densities (8.2±3.4 pg·10^–6 cells at 100% confluence). Stimulation with the pro-inflammatory cytokines IL-1ß (0.3–30 U·mL^–1) or TNF- (0.1–30 ng·mL^–1) dose- and time-dependently (8–72 h) elevated the NGF secretion (effective concentration causing 50% of the maximum response (EC50)=2.9 U·mL^–1 and 1.0 ng·mL^–1, respectively). Treatment with the glucocorticoid budesonide (10^–7 M) markedly reduced the constitutive secretion of NGF by 42%, and attenuated the cytokine-stimulated NGF secretion to the same level.

In conclusion, human lung fibroblasts may serve as a source of nerve growth factor in the lung, positively regulated by the asthma-associated and pro-inflammatory cytokines interleukin-1ß and tumour necrosis factor-, and negatively regulated by the anti-inflammatory glucocorticoids.