Transforming growth factor (TGF)β1 is an intercellular signaling molecule that demonstrates a plethora of biologic effects in both in vitro and in vivo contexts. It was first isolated and characterized in platelets in 1983 1 and is now the prototype member of a superfamily of cytokines, which actually counts 33 members in man 2. For taxonomic purpose, members of the TGFβ superfamily are further divided into subgroups, and together with its two closest homologues TGFβ2 and TGFβ3, TGFβ1 forms the TGFβ subfamily.

TGFβ1 is synthesized as a prepropeptide of 390 aa and is encoded by a 7-exon gene (TGFB1) localized on chromosome 19q13.2. Several genetic studies have associated some of the common single nucleotide polymorphisms (SNP) found in the TGFB1 gene or its promoter with asthma phenotypes, supporting its potential role in the pathogenesis of this disease 345678. The gene is ubiquitously expressed, but its level of expression is transcriptionally and post-transcriptionally regulated. The maturation, expression and activation of the protein are also subject to extensive and complex post-translational regulation. Following its cleavage from the 29 aa signal peptide, the propeptide homodimerizes and both protomeres are cleaved by furin, a ubiquitous subtilisin-like proprotein convertase localized in the trans-Golgi network, at a canonic RX(K/R)R furin cleavage site found at position 275–278 on the TGFβ1 propeptide 9. This proteolytic maturation generates the homodimeric mature protein, in which each of the 112-aa long protomeres remains associated due to hydrophobic interactions and a disulfide bridge 10. This active form of TGFβ1 demonstrates a short half-life (normally less than 3 min) in cell-free systems 11. To overcome its lability in in vivo conditions and to avoid premature binding with its cognate cell-surface receptor, TGFβ1 remains non-covalently associated with its propeptide latency-associated peptide (LAP). This post-translational modification renders TGFβ1 inactive during and after the secretory process. Latent TGFβ1 can also be secreted as a larger 180–210-KD multi-protein complex, which includes, in addition to the 75-KD LAP and the 25-KD mature TGFβ1 protein, the glycosylated 125–190-KD latency TGFβ binding protein (LTBP) 12.

Extracellular activation of latent TGFβ1 occurs through different mechanisms including: 1- proteolytic dissociation from LAP by the urokinase plasminogen activator (uPA)/plasmin system 1314, or by other proteases such as metalloproteinase (MMP)-2 9, MMP-9 1516 and the lysosomal serine protease cathepsin D 13; 2- conformational alteration in its structure by thrombospondin 17 or integrins such as the αvβ6 integrin 1819; 3- oxidation and nitrosylation 2021; 4- removal of carbohydrate structure on LAP by glycosidases such as sialidase 22; 5- integrin αvβ8-mediated latent TGFβ1 recruitment to the cell membrane for membrane type 1 (MT1)-MMP-dependent proteolytic activation 23; and 6- extremes of pH or high concentrations of urea 24. Mannose 6-phosphate/insulin-like growth factor II (IGF-II) receptor 2526 as well as integrins α8β1 27 and αvβ1 28 also bind latent forms of TGFβ1 and are thus believed to target the latent complex on the surface of cells for subsequent proteolytic activation and ensuing binding to its signaling receptor. TGFβ1 is also a heparin binding growth factor (HBGF) 2930. Consequently, its binding availability for cell surface receptors is regulated extracellularly by heparan sulfate proteoglycans (HSPG). Whereas certain proteoglycans, such as betaglycan and endoglin 31, facilitate TGFβ1 binding to its receptors; others, such as biglycan, fibromodulin and decorin, sequester TGFβ1 in the ECM 3233. In addition, certain enzymes that cannot activate latent TGFβ1 directly, such as thrombin, neutrophil elastase or mast cell chymase may also be involved in the process of TGFβ1 activation owing to their ability to release TGFβ1 from pericellular stores 3435.

Six receptors have been identified for TGFβ1 36, but the most studied are the 65-KD type I receptor (Tβ RI or ALK-5), the 85-KD type II receptor (Tβ RII), the 280-KD type III receptor (Tβ RIII or betaglycan, a heparan sulfate/chondroitin sulfate proteoglycan), and more recently the 504-KD Tβ R5, which is also known as the low-density lipoprotein receptor-related protein 1 (LRP1). The canonic mechanisms by which TGFβ1 binds and activates its cognate type I and type II cell surface receptors as well as the intracellular signaling pathways that transduce TGFβ1 messages from the cell membrane to the nucleus have been reviewed extensively 10. Briefly, TGFβ1 initially binds to the single transmembrane, constitutively active, serine/threonine kinase Tβ RII homodimer. The formed complex subsequently recruits the single transmembrane, activable, serine/threonine kinase Tβ RI homodimer, which is concomitantly activated by Tβ RII-mediated phosphorylation of several threonine and serine residues in its intracellular GS juxtamembrane domain. This phosphorylated GS domain then serves as a docking site for activin-receptor activated Smads (AR-Smads; namely Smad2 and Smad3), which are, in turn, phosphorylated by Tβ R1. The phospho-AR-Smads (pSmad2 and pSmad3) then homo or hetero-oligomerize with each other and with at least one co-mediator Smad (Co-Smad; most often called Smad4) and the complex ultimately translocates to the nucleus where it binds Smad binding element (SBE)-containing promoters or interacts with other transcriptional partners to regulate gene expression. Apart from the Smad pathway, it is now clear that other intracellular signaling pathways such as mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase (PI3K), the PP2A phosphatase-mediated p70^S6K inactivation and the Rho-family of small guanosine triphosphatase (GTPase) pathways are activated by TGFβ1 and transduce some of its biological activities (reviewed in 37 and 38). In addition, Smads were shown to cross talk with other important signaling pathways such as Janus kinase-Signal transduction and activator of transcription (JAK-STAT) 39 and WNT 40.

The overall activity of TGFβ1 can thus be regulated at different levels. Any default in proteins involved in the processes that regulate TGFβ1 expression, maturation, secretion, extracellular trafficking and localization, activation/inhibition and binding on its multiple receptors, as well as any default in receptor expression/function/distribution or in the different signaling intermediate molecules that transduce its biological effects intracellularly are susceptible to influence TGFβ1 response.

TGFβ2 and TGFβ3 also bind and signal through the same cell-surface Tβ RI and Tβ RII. Consequently, these cytokines share several biological activities in vitro and it is thus believed that they can substitute for each other's function in vivo. However, knock-outs of each of these individual genes have demonstrated non-overlapping functions of these proteins in vivo 414243. These results may stem from their different promoters, which suggests different expression patterns and regulation 44. In addition, TGFβ2, but neither TGFβ1 nor TGFβ3, required Tβ RIII (betaglycan) to manifest its effector functions. Whether this is related to a three-amino acid divergence that affects the binding affinity to Tβ RII between the sequence of TGFβ2 and the two other isoforms 45 or the lack of RGD sequence in TGFβ2 (which is necessary for cell-surface integrin interaction and concomitant three dimensional-positioning that allows the ligand to access its cognate receptor on cellular plasmalemma) is still a contemporaneous debate, but Tβ RIII is definitely a prerequisite for TGFβ2 activity 46. This peculiarity confers cell-specific activity to TGFβ isoforms, such that only cells expressing the Tβ RIII can response to TGFβ2, and may thus contribute to the non-redundant effects of these cytokines in vivo.

Disregulation of TGFβ1 activity has previously been shown to be involved in a diverse spectrum of pathologic conditions, such as cancer, autoimmunity and fibrotic diseases. The potential role for TGFβ1 in asthma pathogenesis has also been reviewed recently 444748. However, this last assertion is based on the conjecture that TGFβ is overexpressed in asthma. Unfortunately, the studies investigating the expression of TGFβ1 in asthma have yielded inconsistent results. The first purpose of the current work is to review the published data concerning the expression of TGFβ1 in asthma and to discuss the cellular sources to this cytokine in this particular disease. Secondly, recent evidence that TGFβ1 signaling is activated in the airways of asthmatics is presented and a hypothesis is proposed that TGFβ1 overactivation in asthma may not rely exclusively on its increased expression, but may be related to different alterations in other points of regulation that modulate TGFβ1 activity.

Expression of TGFβ1 is altered in asthma and the current weight of evidence suggests that TGFβ1 is upregulated in human and animal asthmatic airways (summarized in Table 1 [see additional file 1], Table 2 [see additional file 2], and Figure 1). However, 6 studies performed with human tissues have shown no regulation of TGFβ1 expression in asthma. In contrast to their previous articles, in which they reported an increased expression of TGFβ1 in bronchoalveolar lavage fluid (BALF) before and after allergic challenge 49, Redington and coworkers 32 have demonstrated indistinguishable pattern of TGFβ1 immunohistochemical staining between asthmatic and control subjects. Aubert and coworkers 50 had previously reported similar findings, but their results were contested since their control subjects were heavy smokers. The relative intensity of TGFβ1 immunostaining in the bronchial mucosa was also similar between asthmatics and healthy subjects in Hoshino and coworkers' study 51. More recently, two papers published by the same group confirmed these results by documenting a lack of significant augmentation of TGFβ1 immunoreactivity in asthmatic epithelium 52, as well as no difference in the number of cells staining positive for TGFβ1 in the submucosa of normal subjects and asthmatic patients suffering from different severity of the disease 53.

Reasons for these discrepancies are currently unknown. However, all conflicting results came from studies measuring TGFβ1 expression by immunohistochemical approaches, using tissue specimens obtained by bronchial biopsies or lung resections. Immunohistochemistry requires extensive tissue handling. All the steps before microscopic reading, including immediate precaution to preserve tissue integrity, reagents used for fixation or to embed the tissue, strength and specificity of the detection and the staining antibodies, and bleaching of the fluorochrome or attenuated chemiluminescence signal occurring during the procedures could all lead to erroneous results and false interpretations. It is thus reasonable to surmise that the conflicting results concerning the increased expression of TGFβ1 in the airways of asthmatics may be the result of technical artefacts. However, alternative hypotheses may explain this conundrum.

Studies investigating the cellular source of TGFβ1 in asthma have also yielded inconsistent results. It is known that TGFβ1 is widely expressed throughout the body and that every resident structural and immune cell in the lung, as well as every inflammatory cell mobilised to the airways during asthma exacerbation, is able to express and secrete TGFβ1. In the lungs of non-asthmatic humans or animals, airway epithelium seems to be the major site of TGFβ1 expression 16637677787980. However, other stromal cells in the airways such as fibroblasts 61818283, endothelial cells 84, vascular smooth muscle (VSM) cells 78 and airway smooth muscle (ASM) cells 50627778858687888990 are also potential source of this cytokine since they were all shown to express and produce detectable amount of TGFβ1. Due to its affinity to certain components of the ECM, latent forms of TGFβ1 in the lung have a tendency to accumulate in particular compartments of the airway wall. In fact, many immunohistochemical studies have localized TGFβ1 mainly in extracellular compartments in association with connective tissues of the airway wall 325062. However, the cellular sources of ECM-sequestered TGFβ1 are difficult to determine. In contrast to these results, Magnan and coworkers 63 were unable to identify TGFβ expression in extracellular space, but rather identified inflammatory cells infiltrating the submucosa and the epithelium as the major source of this cytokine. One could speculate that this controversy may be related to the use of a pan-TGFβ antibody (Ab) in this latter study, but the detection of all three forms of TGFβ instead of TGFβ1 only would be an additional reason to find TGFβ in extracellular spaces.

Active TGFβ signaling, measured by nuclear immunostaining of phosphorylated Smad2 (pSmad2), has been observed in airways of animal 125126127 and human 128129 asthmatics before and after allergic challenge. Recent observations made by Torrego and coworkers 60 further corroborates these results by showing an increased nuclear staining of Smad4, together with an increased expression of nuclear Smad2/3, in the bronchial mucosa of mild atopic asthmatics 24 h post-allergen challenge. Whether these observations are the result of an increased expression of one or many of the TGFβ isoforms, their desequestration from ECM or simply their activation could be debated, but active signaling surely testifies that one or several of these processes are operational in asthma.

However, it is noteworthy to mention that this increased pSmad2 observed in asthma does not exclude the possible involvement of other TGFβ family members in the activation of AR-Smads (Smad2/3). Activin A, in particular, has recently gained interest in asthma pathophysiology. Both mRNA levels in total lung 72 and BALF concentrations 130 of Activin β A were upregulated following OVA sensitization and challenge in mice. In humans, serum levels of Activin A were shown to be elevated in moderate asthmatics (1.16 ng/ml) compared to healthy individuals (0.14 ng/ml) 72. These studies suggest that increased expression of pSmad2 following SAC may not be entirely related to TGFβ1, but may also be due to other cytokines of the TGFβ superfamily that signal via the AR-Smads, such as Activin A. However, the serum levels of TGFβ1 is more than 20-fold higher than those of Activin A 72. In addition, the latter is 10-fold less potent than TGFβ1 in activating the Smad2/3 complex, as measured by transfection of human lung fibroblasts (IMR-90) with a Smad2/3-responsive reporter gene 72. It is thus believed that TGFβ1 might outweigh the effect of Activin A, and consequently, may represent the main contributor to Smad nuclear translocation following allergen challenge.

TGFβ2 is also of particular interest in asthma. Two studies that failed to identify an increased expression of TGFβ1 in asthmatic airways have looked at TGFβ2 expression, and both revealed significant increases 525360. In one of these studies, Chu and coworkers 52 demonstrated a higher level of TGFβ2 in the airway epithelium of asthmatics compared to normal subjects. They further demonstrated that TGFβ2, but not TGFβ1, is increased in primary cultures of bronchial epithelial cells following IL-13 stimulation. This result was supported by two previous articles, in which both IL-13 and IL-4 increased TGFβ2 production in bronchial epithelial cells 109131. In the second study, Balzar and coworkers 53 quantified the number of cells staining positive for TGFβ in the submucosa. They demonstrated that among the 3 TGFβ isoforms, only TGFβ2 was increased in asthmatics. This increased expression was also restricted to the group of patients demonstrating the more severe form of the disease with persistent eosinophilia, which is surprisingly similar to the finding published earlier by the same group using a pan-TGFβ Ab 132. Moreover, they showed that tissue eosinophils from the severe group of patients expressed higher amounts of TGFβ2 compared to tissue eosinophils of control subjects or from patients suffering from a milder form of the disease. Hence, in addition to the increased production of TGFβ2 by the airway epithelium in response to T_H2 cytokines 52109131, eosinophils in the submucosa could contribute to the overall increase of TGFβ2 in the airways of severe asthmatics 53.

Elevated expression of TGFβ2 following bronchoprovocation was also demonstrated in two recent papers 5560. In these studies, TGFβ2 expression was increased in BALF 55 and in the bronchial mucosa 60 24 h after allergen challenge. However, Batra and coworkers 55 also noted a higher expression of TGFβ2 in non-asthmatics at baseline as well as 1 and 2 weeks after SAC compared to asthmatic subjects. In fact, only at 24 h post-SAC did TGFβ2 levels in BALF of asthmatics reach the concentration found in non-asthmatics. Collectively, these results suggest that TGFβ2 is increased in the airway epithelium of asthmatics 52, as well as in eosinophils of a subgroup of severe asthmatics 53, and even if its baseline expression in the fluid harvested by bronchoalveolar lavage is lower compared to non-asthmatics, it is transiently increased after allergen challenge 55. Since the TGFβ2 isoform acts on the same receptors and signal via the same AR-Smads as TGFβ1, these results indicate that TGFβ2 is also a likely candidate to explain activation of Smad signaling in asthma.

However, antibody to TGFβ1 was shown to prevent phosphorylation of Smad2 in a murine model of prolonged allergen challenge-induced asthma 126. This finding suggested that TGFβ1 is responsible for the increased expression of pSmad2 in the airways of asthmatics and excluded the possible involvement of TGFβ2 or Activin A. Interestingly, this anti-TGFβ1 Ab was administered following the establishment of eosinophilic inflammation, and in addition to abrogating pSmad2 signaling in situ, it reduced total and proliferating ASM cell numbers, mucus production and peribronchiolar ECM deposition. These results suggest that anti-TGFβ1 therapy can be envisaged as a therapeutic approach (i.e. following the establishment and the diagnosis of the disease), not only to reverse fibrosis, but also to alleviate other features of airway disease in asthma.

In addition to active TGFβ signaling demonstrated by others 125126127128129, Leung and coworkers 133 showed an increased expression of Smad2/3 in ASM tissue of Brown Norway rats sensitized and exposed to allergen. This result indicates that the asthmatic state may prime ASM tissue to respond in an excessive manner to TGFβ. This altered expression of Smad2/3 was abrogated with oral administration of SD-208, a pharmacological inhibitor targeting ALK5, which suggests that TGFβ is involved in the upregulation of its own signaling intermediates that ensure its signal transduction. Interestingly, both preventive and curative treatments with SD-208 successfully abrogated ASM cell hyperplasia. These treatments equally reduced airway inflammation and goblet cell hyperplasia, suggesting a potent pro-inflammatory action of TGFβ in asthma in addition to its well-recognized function in airway remodeling. These finding also highlight, once again, the beneficial effect of a strategy preventing TGFβ signaling in reversing established features of airway disease.

The anti-inflammatory effects observed with SD-208 are counterintuitive to the well-known immunomodulatory function of TGFβ1 133. In fact, several pieces of evidence have shown that TGFβ1 counteracts excessive airway inflammation. Examples include the following: 1-TGFβ1 heterozygous mice, which express 30% of the TGFβ1 protein level observed in the wild type animal, develop a more severe form of the disease when exposed to an OVA sensitization/challenge protocol 134; 2- T lymphocytes engineered to produce TGFβ1 or conditioned to secrete higher amounts of TGFβ by oral tolerance reverse and ameliorate, respectively, allergen-induced airway inflammation 135136; and 3- blocking TGFβ signaling in T cells by overexpressing Smad7 enhances allergen-induced airway inflammation 129. However, the findings obtained with SD-208 indicate that considering TGFβ1 only as an immunosuppressive cytokine can be misleading. In support of the inflammatory role of TGFβ1 in asthma, others have shown that its release by structural cells in the airways contributes to inflammatory cell recruitment 88115. In fact, TGFβ1 is a powerful chemotactic factor for monocytes/macrophages 137, eosinophils 138, neutrophils 139 and mast cells 140in vitro. Migration of monocytes/macrophages toward a gradient of TGFβ1 occurs at concentrations in the femtomolar range 137. Additionally, TGFβ1 has been shown to rescue murine macrophages from apoptosis 141. In vivo, the number of mast cells in ASM bundles was positively associated with the ASM tissue expression of TGFβ1 88. Given the important function of mast cells in the pathophysiology of allergic asthma 116, increased secretion of TGFβ1 by structural cells in the airways following allergic challenge may foster, rather than attenuate, inflammation.

With all data taken together, one might imagine the following scenario of TGFβ1 regulation in asthma and its potential role in the pathogenesis of the disease. In the first stage of the disease, structural cell-derived TGFβ1 may be released, or simply activated, to induce tissue infiltration of antigen presenting cells (APC, i.e. monocytes and dentritic cells) and mast cells. Both of these cell types are required for an immunologic response to take place in the airways. On one hand, APC capture and process the allergen and then migrate to regional lymph nodes to build a T- and B-lymphocyte immunologic response. On the other hand, mast cells home to the airway walls and will bind to B-cell-derived IgE to produce an allergen-specific reaction upon subsequent allergen exposure. In this scenario, it is thus inferred that TGFβ1 is implicated in the inception of allergic asthma by fostering the sensitization process. In later stages of the disease (i.e. in already sensitized individuals), TGFβ1 synthesis by structural cells may stay downregulated for a while to favor the establishment of lymphocytic and neutrophilic/eosinophilic inflammation. These mobilised inflammatory cells are first programmed to synthesize or secrete pro-inflammatory mediators and to sequentially express and secrete immunosuppressive cytokines, such as TGFβ1, to prevent excessive inflammation and damage. At later time points, when the bulk of inflammation is resolved, alveolar macrophages would maintain their higher secretion of TGFβ1 and the airway epithelium would start to express TGFβ1 again 54. Increased expression of TGFβ1 by both of these cellular sources may aim to get rid of remnant inflammation and to pursue the healing response. In this scenario, when TGFβ1 action is well regulated, restitution of airway wall integrity would take place and airway function would be recovered. Otherwise, when TGFβ1 actions are uncontrolled, airway remodeling would likely occur.

TGFβ receptors are also expressed ubiquitously on mammalian cells 142143144145. In the lung, Tβ RI and Tβ RII were identified in macrophages, as well as in epithelial, VSM, ASM and endothelial cells of both conducting airways and alveoli 78. In contrast to its ligands, only few studies have documented the regulation of these receptors in asthmatic airways. Balzar and coworkers 53 have demonstrated that Tβ R1 is downregulated in mild and severe asthma. Similarly, Barbato and coworkers 146 have reported a decrease in the number of cells positive for Tβ RII in the subepithelium of children with asthma. According to the authors, these results may be indicative of active TGFβ signaling, which is associated with TGFβ receptor internalization. In contrast, wounding 119 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment 147 have been shown to increase TGFβ receptor expression in monocultures of ASM cells. Since ASM cells are subjected to different kinds of damaging stress and that GM-CSF is upregulated in the lungs of asthmatic patients 61148149, these in vitro observations will require further attention as they may actually subtantiate the biological effect of TGFβ1 on ASM cells in vivo.

Despite being extensively studied, the expression of TGFβ1 in the airways of asthmatics still elicits more questions than answers. The current weight of evidence suggests that TGFβ1 is upregulated in asthma. However, whether its expression is altered at baseline or it is upregulated in a transient fashion following bronchoprovocation is not clear and may depend on the particular cell and/or tissue studied. For instance, baseline expression of TGFβ1 seems to be increased in alveolar macrophages 99100, but its expression in the airway lumen appears to be inducible. In support to the latter contention, two groups of investigators that have collected BALF following SAC in human asthmatics have demonstrated that the TGFβ1 level is transiently increased 4955150. On the other hand, the kinetics of TGFβ1 expression in the airway epithelium of asthmatics seem to be more complex since both upregulation 61107 and downregulation 63 have been reported. Studies looking at the kinetics of TGFβ1 expression in this particular tissue following allergen challenge should shed light on these conflicting results.

As pointed out in this review, all the studies that were unable to detect an altered protein expression of TGFβ1 in asthma were investigating its expression levels by immunohistochemistry. However, it is also important to mention that certain investigators were capable to demonstrate an increased expression of TGFβ1 in asthmatic airways at baseline (i.e. without prior allergen challenge or apparent asthma exacerbation) by using immunohistochemistry. For example, Minshall 65, Chakir 68, Kokturk 62, Berger 88 and Xie 90 with their respective coworkers have all previously shown an increased intensity of staining or an increased number of positive cells for TGFβ1 in the subepithelial region of asthmatic airways. In most cases, it seems to be associated with the severity of the disease 656888 and the immunohistochemical signal seems to originate from inflammatory cells infiltrating the submucosa 6568 or ASM 8890. Owing to the static picture obtained by staining lung sections by immunohistochemical techniques and because endobronchial biopsies in humans are performed when the patients are free of symptoms, the lack of increased expression of TGFβ1 reported by these groups of investigators can reflect the failure to capture the transient TGFβ1 upregulation. This may be the reason why more immunohistochemical studies seem to be involved in the controversial issue highlighted in this review. Alternatively, reported inconsistencies may be the result of technical artefacts related to immunohistochemistry or to inherent heterogeneity of asthma pathogenesis among different populations.

Limitations with BALF procedure were also highlighted in this review and it may thus be too soon to reject the possibility that TGFβ1 in not overexpressed in asthma. Studies designed to harvest tissues at multiple-time points following allergic challenge would be very useful to understand the kinetics of this cytokine regulation. Considering the invasive nature of trans- or endo-bronchial biopsies or BALF, repeated measurements seem quite unrealistic in human subjects. Less invasive techniques of investigation, such as induced sputum 58151 or exhaled breath condensate 101, represent interesting alternatives for these multiple time point studies and have previously been used successfully to assess TGFβ1 expression in human subjects. The question that remains is to what extent these techniques accurately reflect TGFβ1 expression in deeper airways. As such, the validity of these techniques needs to be tested. Otherwise, identification of other surrogates of lung TGFβ1 expression that could be readily measured by these less invasive techniques would be required. A last possibility to understand the kinetics of TGFβ1 expression and activation would be to consider the use of animal models.

In the meantime, increased expression of TGFβ1 has been shown to occur exclusively in restricted localization in the airways or only in particular subgroups of patients, such as in severe asthmatics demonstrating prominent eosinophilic inflammation 132. Hence, in addition to temporal concerns, spatial concerns need to be considered. The fact that TGFβ1 may be differently involved in the pathogenesis (or in the remission) of asthma in phenotypically distinct groups of asthmatics must also be appreciated. In addition, a debate still persists concerning the inflammatory cell that is mainly involved in the generation of TGFβ1 in asthma, as eosinophils, macrophages, neutrophils, epithelial cells and ASM cells have all been pointed out. Whether these conflicting results mirror the heterogeneity of the disease in term of triggering agents, individual genetic variability, history and severity of the disease, or whether they are simply related to the time points or the tissue chosen to measure TGFβ1 expression are still unresolved questions and will required further explorations.

Since TGFβ1 is released in an inactive form, its kinetics of activation will also be relevant to elucidate its biological or pathobiological functions in asthma. As highlighted in this review, several points of regulation can influence the final magnitude of the TGFβ1 response. All of these points of regulation are as important as the expression of TGFβ1 per se if one attempts to appreciate the overall contribution of this cytokine in airway pathogenesis that characterizes asthma. Unfortunately, studies investigating these points of control are limited. On the other hand, several studies indicate that TGFβ1 activity is increased in the airways of asthmatics, as measured by intermediary end points of TGFβ1 signaling (pSmads), which indicate that TGFβ1 has been activated and has bound to its cognate cell-surface receptor. These results suggest that if TGFβ1 is not upregulated in asthma, other points of control must be altered and this is ultimately translated into an increased TGFβ1 activity. However, these results do not exclude the involvement of other TGFβ superfamily members that signal via the same Smads. But in this regard, one study suggested that among these family members that demonstrated an upregulated expression in asthma, TGFβ1 is likely the main contributor to the increased Smad signaling 126.

Dissecting the kinetics of TGFβ1 regulation following bronchoprovocation will undoubtedly increase our understanding of the inflammatory and fibrotic processes that take place in asthma. Due to its large spectrum of biologic effects, it is also unfortunately too soon to determine whether TGFβ1 is the good guy or the nasty guy in asthma. However, results obtained recently with anti-TGFβ1 Ab 126 or with an ALK-5 inhibitor (SD-208) 133 in animal models of the disease are promising and suggest that targeting TGFβ1 may be beneficial in the treatment of human asthma.

The author(s) declare that they have no competing interests.