Unité Mixte de Recherche 7034, Centre National de la Recherche Scientifique, Faculté de Pharmacie, Illkirch, France
TRANSFORMING GROWTH FACTOR (TGF)-1 belongs to the TGF-
family of proteins corresponding to a set of pleiotropic secreted signaling molecules with unique and potent immunoregulatory properties (10). TGF-
1 is produced by every leukocyte lineage, including lymphocytes, macrophages, and dendritic cells, and its expression serves in both autocrine and paracrine modes to control the differentiation, proliferation, and state of activation of these immune cells (10). Because the TGF-
1 gene product is upregulated in bronchial tissue from severe asthmatic subjects vs. normal subjects (1, 14) as well as in bronchoalveolar lavage fluids from patients suffering from asthma (18), TGF-
1 has been associated with the airway structural changes (airway remodeling) that occur in chronic asthma.
The mechanisms by which TGF-1 contribute to the pathogenesis of asthma are unknown, but growing evidence suggests that TGF-
1 regulates airway remodeling by acting directly on resident airway cells, such as epithelium, fibroblast, and airway smooth muscle. Thus TGF-
1 was reported to induce airway smooth muscle cell proliferation, to enhance synthesis and release of extracellular matrix, and to induce collagen synthesis by airway smooth muscle (3). Others showed that TGF-
1 increased expression of connective tissue growth factor through ERK- and JNK-dependent pathways (20). TGF-
1 is also considered as an essential mediator for the transformation of fibroblasts into myofibroblasts that are major producers of collagen. Interestingly, allergen challenge in sensitized mice induces an increase in lung tissue levels of TGF-
1 and cell-associated TGF-
1 production with a concomitant airway remodeling process (11). Anti-TGF-
1 antibodies prevent the occurrence of airway remodeling via an effect on the Smad signaling pathway (12). Together with numerous other studies (2), these observations suggest that TGF-
1 signaling not only contributes to the progression but also to the persistence of structural features, including airway remodeling, seen in asthma.
That, in addition to TGF-1, bradykinin also plays a role in the physiopathology of asthma is undeniable. Indeed, bradykinin and related kinins play important roles in the pathogenesis of inflammation, tissue damage, and repair (4, 17). Bradykinin induces airway obstruction in patients with asthma but not in normal subjects (6). Both bradykinin receptor subtypes seem to contribute to allergen-induced bronchial hyperresponsiveness of rat (7), whereas in humans, airway hyperresponsiveness to bradykinin appears to be mediated solely by the bradykinin 2 (B2) receptor (16, 19). Whether a cross talk between TGF-
1 and bradykinin pathways exists has never been investigated in airway smooth muscle hyperresponsiveness. Especially, TGF-
1 and bradykinin use different signaling pathways to release IL-8 from primary airway smooth muscle cell cultures (15). Indeed, IL-8 release induced by bradykinin, but not by TGF-
1, in primary airway smooth muscle cell cultures is dependent on prostanoid generation via cyclooxygenase-2 isozyme induction (5). Many fascinating questions remain open about a putative role of TGF-
1 in promoting airway hyperresponsiveness to bradykinin in asthma.
In the report by Kim et al., the current article in focus (Ref. 9, see p. L511 in this issue), the authors produce an initial answer to these questions by establishing a link between TGF-1 and the exaggerated airway responsiveness to bradykinin seen in asthmatic patients. This study shows that TGF-
1-treated airway rings exhibit increased contractile responses to bradykinin. Whether TGF-
1 exerts its effect by directly modulating airway smooth muscle function is not yet known. Interestingly, TGF-
1-exposed cultured human airway smooth muscle cells also exhibit exaggerated cytosolic Ca2+ responses to bradykinin, possibly due to an increase in the B2 receptor number. This increase, however, is not dependent on prostanoid generation. In contrast, what is highly interesting is that this effect was specific for bradykinin since calcium signals remained unaffected under carbachol stimulation. This is an important finding because it suggests that TGF-
1 involves a pathway that selectively provokes local chromatin rearrangements among which the locus of the human B2 receptor gene (14q32.1-q32.2) is certainly a privileged target. Furthermore, this effect might be complementary to the effect of TGF-
1 on the decrease in
-adrenergic receptors in cultured human tracheal smooth muscle cells leading to exacerbated airway responsiveness to bradykinin (13).
Besides changes in airway remodeling induced by various cytokines, chromatin remodeling appears to be a fundamental process induced by TGF-1, considering that a set of genes is upregulated. Indeed, besides bradykinin B2 receptors, several genes were reported to be upregulated by TGF-
1, with 60 and 170 genes upregulated after 4 and 24 h of cytokine treatment of human airway smooth muscle cell cultures, respectively (8). The TGF-
1-sensitive genes include many growth factors, structural proteins, extracellular matrix, and other secreted glycoproteins including tropomyosin, actin, cartilage oligometric matrix protein, collagens, elastin, and dermatopontin. Several fundamental questions remain to be elucidated. Will the cells remain hyperresponsive to bradykinin following a more chronic stimulation with TGF-
1? Can airway smooth muscle cell hyperresponsiveness to bradykinin be transmitted to the daughter cells without being continuously exposed to TGF-
1? Is this response an irreversible phenomenon? What are the molecular mechanisms behind the hyperresponsive effect of TGF-
1?
The contribution of Kim and coworkers (9) thus sheds light on the physiopathological link between TGF-1 and bradykinin in asthma and also represents a good experimental model in which to study the molecular mechanisms of the switch of airway smooth muscle cells from a "normal" state to a "hyperresponsive" state.
![]() |
FOOTNOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() |
---|
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Visit Other APS Journals Online |