Expression of nerve growth factor in the airways and its possible role in asthma
Introduction
Nerve growth factor (NGF) was discovered by Rita Levi-Montalcini and co-workers more than 50 years ago (reviewed by Levi-Montalcini et al., 1995, Levi-Montalcini et al., 1996). It belongs to the neurotrophin family of proteins, which also includes brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and NT-4/5 (Barde, 1990). NGF is essential for the survival and development of peripheral and brain neurons (Levi-Montalcini, 1966; Levi-Montalcini and Aloe, 1985; Levi-Montalcini, 1987; Thoenen et al., 1987). It may also be involved in inflammation. This review examines the current literature about NGF expression and regulation in the airways and summarizes the findings that suggest that it may have a role in asthma.
Section snippets
Sources of NGF in the airways
Mouse salivary glands, mouse sarcoma and snake venom were the first sources of NGF to be discovered (Aloe and Levi-Montalcini, 1980; reviewed by Levi-Montalcini, 1987), but studies since then have found a broad range of cells able to synthesize and secrete NGF. Its sources in the airways include inflammatory cell infiltrates of the bronchial mucosa as well as structural cells (Fig. 1).
Inflammatory cells
NGF production was first discovered in cells from the peripheral and central nervous system, but studies in the 1990s also reported that it is secreted by cells of the immune system (Aloe et al., 1994; Levi-Montalcini et al., 1995, Levi-Montalcini et al., 1996). Indeed, T and B lymphocytes (Ehrhard et al., 1993; Santambrogio et al., 1994; Torcia et al., 1996; Lambiase et al., 1997), mast cells (Leon et al., 1994; Nilsson et al., 1997), eosinophils (Solomon et al., 1998; Kobayashi et al., 2002)
In vivo studies
The in vitro secretion of NGF in cultured cells accords fully with reports of NGF-positive immunolabeling in bronchial biopsy samples from patients with or without asthma (Kassel et al., 2001; Olgart-Höglund et al., 2002). NGF immunolabeling is intense in bronchial epithelium and the bronchial smooth muscle layer, but less intense in airway fibroblasts (Fig. 3a,b). In bronchial biopsy samples from asthmatic patients, the inflammatory cell infiltrate also shows NGF immunolabeling (Kassel et al.,
Regulation of NGF expression in the airways
The mechanisms regulating the production and release of NGF in the airways in vivo require further study, but for the time being, in vitro experiments provide some information. Examination of the regulation of NGF expression during cell proliferation and quiescence shows that NGF secretion in lung fibroblasts (Olgart and Frossard, 2001) and in airway smooth muscle cells (Freund et al., unpublished data) depends on cell density. That is, NGF secretion is high when the cell culture begins and
Upregulation of NGF in inflammatory conditions
NGF expression also appears to be modulated by inflammatory mediators in the airways. Inflamed airways contain increased levels of NGF (Sanico et al., 2000; Olgart-Höglund et al., 2002), perhaps due in part to an increase in the number of inflammatory cells that infiltrate the bronchial mucosa and release NGF (reviewed by Olgart and Frossard, 2002). Autocrine or paracrine NGF may activate many or most of these inflammatory cells, which then release proinflammatory cytokines, which may in turn
Downregulation of NGF by anti-inflammatory drugs
Because corticosteroids are known to have anti-inflammatory effects and to be clinically effective in suppressing inflammation in the lungs and airways, researchers have examined the effect of two of them, budesonide and dexamethasone, on NGF secretion. Lindholm et al. (1990) reported that glucocorticoids downregulate cytokine-stimulated NGF expression by repressing NGF gene transcription in cultured sciatic rat fibroblasts. Our team found that glucocorticoids downregulate cytokine-induced NGF
Action on neuronal cells
Transgenic mice that overexpress NGF in the lungs show marked airway hyperinnervation of sensory and sympathetic fibers; under electric field stimulation, they release increased quantities of substance P (SP) (Hoyle et al., 1998). This result is consistent with findings that NGF can stimulate neuron development, growth and survival, particularly of the sensory and sympathetic innervation (Levi-Montalcini, 1987). Indeed, these neurons express NGF receptors (Verge et al., 1989; Lee et al., 1992;
Action on inflammatory cells
NGF activates cells through two types of cell surface receptors: the receptor tyrosine kinase A (TrkA), which has a high affinity for NGF, and the p75 neurotrophin receptor (p75NTR), with low affinity for NGF (Barbacid, 1995; Greene and Kaplan, 1995; Segal and Greenberg, 1996; Kaplan and Miller, 1997). Most inflammatory cells can produce NGF and also express both of these NGF receptors. For example, TrkA receptor has been found on human mast cells (Tam et al., 1997; Nilsson et al., 1997), in
NGF action on structural cells
Although the action of NGF on airway structural cells remains to be further elucidated, recent studies certainly suggest that there are effects (Table 1). NGF stimulates the contraction and migration of lung fibroblasts (Micera et al., 2001, Kohyama et al., 2002) and vascular smooth muscle cells (Kraemer et al., 1998); it also induces the proliferation of airway smooth muscle cells (Freund et al., 2003). These results suggest that NGF plays a role in the airway remodeling that occurs in asthma.
Possible role of NGF in asthma
Accumulating studies suggest that NGF is involved in the development of inflammation in airway diseases, asthma in particular.
Conclusion
In summary, NGF levels in the airways increase in asthma and are further upregulated after allergenic challenge. NGF also appears to contribute to inflammation and bronchial hyperresponsiveness in asthmatic airways. Because in vitro studies show that NGF is upregulated by inflammatory cytokines and decreased by anti-inflammatory glucocorticoids, and because NGF effects are demonstrated in the airway remodeling, this neurotrophin should be considered a new mediator in airway inflammation. In
References (120)
- et al.
Comparative studies on testosterone and L-thyroxine. Effects on the synthesis of nerve growth factor in mouse submaxillary salivary glands
Exp. Cell Res.
(1980) - et al.
NGF primed spleen cells injected in brain of developing rats differentiate into mast cells
Int. J. Dev. Neurosci.
(1989) Neurotrophic factors and their receptors
Curr. Opin. Cell Biol.
(1995)The nerve growth factor family
Prog. Growth Factor Res.
(1990)- et al.
Macrophages express neurotrophins and neurotrophin receptors. Regulation of nitirc oxide production by NT-3
J. Neuroimmunol.
(2001) Differential effects of Th1 and Th2 derived cytokines on NGF synthesis by mouse astrocytes
FEBS Lett.
(1996)- et al.
Functional IL-4 receptors on mouse astrocytes: IL-4 inhibits astrocyte activation and induces NGF secretion
J. Neuroimmunol.
(1998) - et al.
Interaction between nerve growth factor and lysophosphatidylserine on rat peritoneal mast cells
FEBS Lett.
(1982) - et al.
Nerve growth factor induces the expression of certain cytokine genes and bcl-2 in mast cells. Potential role in survival promotion
J. Biol. Chem.
(1996) - et al.
Nerve growth factor binds to normal human keratinocytes through high and low affinity receptors and stimulate their growth by a novel autocrine loop
J. Biol. Chem.
(1993)
Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo
Neuroscience
Release of nerve growth factor by human pulmonary epithelial cells: role in airway inflammatory diseases
Eur. J. Pharmacol.
Early events in neurotrophin signaling via Trk and p75 receptors
Curr. Opin. Neurobiol.
Neurotrophin-4 production by human epidermal keratonicytes increased expression in atopic dermatitis
J. Invest. Dermatol.
Tumor necrosis factor stimulates the synthesis and secretion of biologically active nerve growth factor in non-neuronal cells
J. Biol. Chem.
Tumor necrosis factor is markedly synergistic with interleukin-1 and interferon gamma in stimulating the production of nerve growth facotr in fibroblasts
FEBS Lett.
Effects of nerve growth factor on rat peritoneal mast cells: survival promotion and immediate-early gene induction
J. Biol. Chem.
Signal transduction by the neurotrophin receptors
Curr. Opin. Cell Biol.
Nerve growth factor prevents apoptosis of rat peritoneal mast cells through the trk proto-oncogene receptor
Blood
Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli
Blood
Nerve growth factor stimulates fibronectin-induced fibroblast migration
J. Lab. Clin. Med.
Human CD4+ T cell clones produce and release nerve growth factor and express high affinity nerve growth factor receptors
J. Allergy Clin. Immunol.
Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system
Cell
Update of the NGF saga
J. Neurol. Sci.
Nerve growth factor: from neurotrophin to neurokine
Trends Neurosci.
Interleukin-1 increases stability and transcription of mRNA encoding nerve growth factor in cultured rat fibroblasts
J. Biol. Chem.
Activation of Vav and Ras through the nerve growth factor and B cell receptors by different kinases
Cell Immunol.
Human fibroblast cells synthezise and secrete nerve growth factor in culture
Biochem. Biophys. Res. Commun.
Gene expression of neurotrophins and their receptors in cultured rat vascular smooth muscle cells
Biochem. Biophys. Res. Commun.
Nerve growth factor secretion by human lung epithelial A549 cells in pro- and anti-inflammatory conditions
Eur. J. Pharmacol.
The role of neurotrophins in bronchial asthma
Eur. J. Pharmacol.
Mast cell increase in tissues in neo-natal rats injected with the nerve growth factor
Brain Res.
Nerve growth factor and autoimmune diseases
Autoimmunity
Interleukin-4 and -5 as modulators of nerve growth factor synthesis/secretion in astrocytes
J. Neurosci. Res.
Inflammatory mediators of asthma: an update
Pharmacol. Rev.
Effect of nerve growth factor on the release of inflammatory mediators by mature human basophils
Nerve growth factor enhances precocious differentiation an numerical increase in mast cells in culture of rat splenocytes
Accad. Naz. Lincei
Circulating nerve growth factor levels are increased in humans with allergic diseases and asthma
Proc. Natl. Acad. Sci. USA
Nerve growth factor: a chemotactic factor for polymorphonuclear leukocytes in vivo
J. Immunol.
Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma
Eur. J. Immunol.
Functional nerve growth factor receptors on human B lymphocytes. Interaction with IL-2
J. Immunol.
Basophil priming by neurotrophic factors: activation through the trk receptor
J. Immunol.
Nerve growth factor induces a neurokinin-1 receptor-mediated airway hyperresponsiveness in guinea pigs
Am. J. Respir. Crit. Care Med.
The role of sensory nerve endings in nerve growth factor-induced airway hyperresponsiveness to histamine in guinea pigs
Br. J. Pharmacol.
Antibodies directed against nerve growth factor inhibit the acute bronchiconstriction due to allergen challenge in guinea-pigs
Clin. Exp. Allergy
Neurotrophin and neurotropin receptors in vascular smooth muscle cells. Regulation of expression in response to injury
Am. J. Pathol.
Expression of functional trk protooncogen in human monocytes
Proc. Natl. Acad. Sci. USA
Expression of functional trk tyrosine kinase receptors after T cell activation
J. Immunol.
Nerve growth factor induces activation of MAP-kinase and p90rsk in human B lymphocytes
J. Immunol.
Upregulation of nerve growth factor expression by hyman airway smooth muscle cells in inflammatory conditions
Eur. Respir. J.
Cited by (41)
Neurotrophic factors and their receptors in lung development and implications in lung diseases
2021, Cytokine and Growth Factor ReviewsFine tuning of insulin secretion by release of nerve growth factor from mouse and human islet β-cells
2016, Molecular and Cellular EndocrinologyCitation Excerpt :NGF acts via two membrane receptors: the low affinity p75NTR, an atypical member of the TNFα superfamily (Zampieri and Chao, 2006), and the high affinity trkA, belonging to the tyrosine kinase receptor family (Muragaki et al., 1995). While trkA works through phosphorylation, mainly regulating the activation of signals promoting cell survival, proliferation and differentiation (Freund and Frossard, 2004), p75NTR does not possess catalytic activity but it recruits intracellular effectors depending on its holo- (NGF-bound) and apo- (unbound) forms (Roux and Barker, 2002). In those systems expressing both receptors, p75NTR can co-operate with trkA forming a “super affinity” receptor, thus enhancing the response to low concentrations of NGF (Huber and Chao, 1995).
Abdominal aortic aneurysm and histological, clinical, radiological correlation
2016, Acta HistochemicaItch sensation through transient receptor potential channels: A systematic review and relevance to manual therapy
2013, Journal of Manipulative and Physiological TherapeuticsCitation Excerpt :Nerve growth factor is responsible for the maintenance and survival of sensory neurons. Nerve growth factor expression is increased in inflammatory diseases because it suppresses inflammation.22 Nerve growth factor leads to increased density of epidermal nerve endings which increases scratching behavior.15
Regulation of IGF-1 but not TGF-β1 by NGF in the smooth muscle of the inflamed urinary bladder
2012, Regulatory PeptidesCitation Excerpt :Recent studies also provide strong evidence demonstrating that NGF is expressed in inflammatory conditions [7–11]. The increased NGF levels are observed in bronchoalveolar lavage fluid and serum from patients with asthma [7] and in the urinary bladder and the urine from patients with bladder inflammation [9–11]. In a CYP-induced bladder inflammation model, rats treated with CYP acutely (single dose for 4 h) or chronically (multiple dose for 10 days) [12] show increased amount of NGF mRNA or protein in the inflamed urinary bladder.
Localization of nerve growth factor (NGF) receptors in the mitochondrial compartment: Characterization and putative role
2012, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Immunoprecipitation with anti-ANT (Fig. 6d) or anti-PDE4A5 (Fig. 6e) of mitochondrial fractions from whole rat brain revealed the presence of specific bands when blotted with anti-p75 indicating an interaction between the low affinity NGFR and the ANT or PDE4A5. Activation of trkA receptor leads to cell survival [2,3] therefore we investigated whether the expression of the high affinity NGF receptors in brain mitochondrial protects these organelles from Ca2+ induced swelling. Isolated mitochondria from cortex and cerebellum were exposed to a solution of 200 μM Ca2+ and concomitantly treated with or without NGF (100 ng/ml).