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

Abstract

Human lung fibroblasts secrete nerve growth factor: effect of inflammatory cytokines and glucocorticoids. C. Olgart, N. Frossard. #ERS Journals Ltd 2001. ABSTRACT: 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-1b (IL-1b), tumour necrosis factor-a (TNF-a) 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-1b (0.3 -30 U?mL -1 ) or TNF-a (0.1 -30 ng?mL -1 ) dose-and timedependently (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-1b and tumour necrosis factor-a, and negatively regulated by the antiinflammatory glucocorticoids.

Nerve growth factor levels and localisation in human asthmatic bronchi

“…In particular, T-helper 2 (Th2) lymphocytes and mast cells express and secrete enhanced levels of NGF in vitro in response to activation [16,[19][20]. Furthermore, structural cells of the lung, such as fibroblasts, epithelial cells and smooth muscle cells, also secrete enhanced amounts of NGF in response to the pro-inflammatory and asthma-associated cytokines interleukin-1b and tumour necrosis factor-a in vitro [25][26][27][28]33]. Thus, multiple sources of the excessively secreted NGF in asthma are probable, either related to structural cells expressing more NGF in asthmatic inflammatory conditions or to a greater number of infiltrated inflammatory cells in the asthmatic airways expressing NGF in the same or in greater quantities.…”

“…A number of studies in several cell systems in vitro further support the constitutive production of NGF. For instance, human lung fibroblasts [27], airway epithelial cells [25,26], airway smooth muscle cells [28], and cells from the immune system, such as lymphocytes [19,20], mast cells [13][14][15][16] and eosinophils [17,18] may produce and secrete NGF in vitro. However, less is known about the situation in vivo and in particular in the human airways.…”

“…Among these are cells from the immune system, including mast cells [13][14][15][16], eosinophils [17,18], lymphocytes [19,20], monocytes [21] and macrophages [4,22], as well as structural cells, such as fibroblasts, epithelial cells and smooth muscle cells [23][24][25][26][27][28]. Many of these cell types are important participants in the inflammatory condition of the asthmatic airways.…”

Nerve growth factor is released by IL-1β and induces hyperresponsiveness of the human isolated bronchus

“…The mechanism of such hyperresponsiveness is unclear. In experiments performed in human airway cells in culture, IL-1b induced the release of NGF from fibroblasts [15], bronchial smooth muscle cells [16] and airway epithelial cells [17,18]. However, whether IL-1b is able to induce release of NGF from the human bronchus ex vivo has not yet been reported.…”

Nerve Growth Factor and Sepsis

“…Human fibroblast, airway smooth muscle, and lung epithelium A549 cells have the ability to synthesize NGF. Synthesis in this cells is induced by proinflammatory cytokines (IL-1 , TNF-) and inhibited by glucocorticoids [34][35][36][37][38][39]. In mouse models of arthritis, stimulation with IL-1 has been demonstrated to increase the synthesis of NGF, which results in the increase of TNF- [40].…”