The cytokine network in asthma and chronic obstructive pulmonary disease (original) (raw)
Lymphokines include cytokines that are released predominantly from T cells, which play a critical role in orchestrating inflammation in asthma (Figure 3) and are also prominent in the inflammation observed in individuals with COPD. The T cells detected in the inflamed airways of individuals with asthma and COPD secrete distinctive patterns of cytokines that are associated with the different patterns of inflammation seen in these diseases through their roles in recruiting distinct types of inflammatory cells and mediating distinct effects on structural cells in the airways.
Th cells in airways. Th2 cells predominate in most patients with asthma and differentiate from uncommitted precursor T cells under the influence of IL-4. Th2 cells orchestrate allergic inflammation through the release of the Th2 cytokines IL-4, IL-5, IL-9, and IL-13. Th1 cells differentiate under the influence of IL-12 and IL-27 and suppress Th2 cells through the release of IFN-γ. Th17 cells differentiate under the influence of IL-6 and IL-23. Tregs normally suppress other Th cells through the release of TGF-β and IL-10 and may have impaired function in asthma. Each Th cell type is regulated by a specific transcription factor: T-bet for Th1 cells, GATA3 for Th2 cells, retinoic acid orphan receptor-γt (RORγt) for Th17 cells, and FOXP3 for Tregs.
Th2 cytokines. In patients with asthma, there is an increase in the number of CD4+ Th cells in the airways, which are predominantly of the Th2 subtype (1). Th2 cells are characterized by secretion of IL-4, IL-5, IL-9, and IL-13. The transcription factor GATA-binding protein 3 (GATA3) is crucial for the differentiation of uncommitted naive T cells into Th2 cells and regulates the secretion of Th2 cytokines (3). There is an increase in the number of GATA3+ T cells in the airways of stable asthmatic subjects (4). Following ligation of the TCR and CD28 coreceptor by APCs, GATA3 is phosphorylated and activated by p38 MAPK, resulting in translocation from the cytoplasm to the nucleus, where it activates transcription of genes characteristic of Th2 cells (5). Nuclear factor of activated T cells (NFAT) is a T cell–specific transcription factor and enhances the transcriptional activation of the Il4 promoter by GATA3 (3). Finally, IL-33, a member of the IL-1 family of cytokines, promotes differentiation of Th2 cells by translocating to the nucleus and regulating transcription through an effect on chromatin structure (6), but it also acts as a selective chemoattractant of Th2 cells (7). Although COPD is viewed as a disease of type 1 immunity (1), Th2 cytokines may also be increased in COPD patients; for example, increased IL-4 expression is seen in CD8+ T (Tc2) cells from bronchoalveolar lavage (BAL) fluid (8).
IL-4 plays a critical role in the differentiation of Th2 cells from uncommitted Th0 cells and may be important in initial sensitization to allergens. It is also important for isotype switching of B cells from producers of IgG to producers of IgE. IL-13 mimics IL-4 in inducing IgE secretion and causing structural changes in the airways but does not play a role in promoting Th2 cell differentiation (9). IL-13 signals through a heterodimeric receptor comprising the α-chain of the IL-4 receptor (IL-4Rα) and a specific IL-13–binding chain (IL-13Rα); the use of IL-4Rα accounts for some of the shared effects of IL-4 and IL-13, which are mediated via activation of STAT6. IL-13 also binds to another receptor (IL-13Rα2), which does not appear to signal and acts as a decoy receptor. IL-13 has attracted particular attention as a therapeutic target for the treatment of asthma, as it not only induces airway hyperresponsiveness (AHR) in animal models of asthma but also produces several of the structural changes seen in chronic asthma, including goblet cell hyperplasia, airway smooth muscle proliferation, and subepithelial fibrosis (9). IL-13 induces inflammation through stimulating the expression of multiple chemokines, including CCL11 (also known as eotaxin) from structural cells in the airways, including epithelial cells. IL-13 induces AHR and mucus hypersecretion by activating STAT6 in the airway epithelium (10), which increases expression of acid mammalian chitinase (AMC) (11). Indeed, neutralization of AMC inhibits IL-13–mediated AHR and Th2-driven inflammation. IL-13 is produced by several cell types in addition to Th2 cells, including other types of T cells (Th1 cells, Tc2 cells, and invariant NKT cells) and inflammatory cells (mast cells, basophils, and eosinophils). IL-13 shows increased expression in the airways of asthmatic patients, whereas it is reduced in patients with severe COPD (12). After allergen challenge, there is a transient increase in IL-4 in BAL fluid, whereas the secretion of IL-13 is sustained and correlates with the increase in the number of eosinophils in the airways (13). Further, levels of a chitinase-like protein are increased in the lungs and serum of patients with severe asthma, possibly reflecting increased IL-13 secretion (14). Pitrakinra, a mutated form of IL-4 that blocks the binding of IL-4 and IL-13 to IL-4Rα, reduces the late response to inhaled allergen in asthmatic patients after either inhaled or subcutaneous administration (15).
IL-5 plays a key role in inflammation mediated by eosinophils, since it is critically involved in the differentiation of eosinophils from bone marrow precursor cells and also prolongs eosinophil survival. Systemic and local administration of IL-5 to asthmatic patients results in an increase in circulating eosinophils and CD34+ eosinophil precursors (16). In experimental animals, blocking antibodies specific for IL-5 reduces eosinophil numbers in the lungs and inhibits allergen responses. However, in asthmatics, a humanized blocking antibody specific for IL-5 (mepolizumab) markedly reduces circulating and sputum eosinophils but has no effect on allergen responses or AHR. In symptomatic asthmatics, mepolizumab has no clinical benefit, despite a marked reduction in circulating eosinophils (17). However, mepolizumab does not completely eliminate eosinophils from the airways, which may explain why it provides no clinical benefit (18).
IL-9 overexpression in mice induces inflammation mediated by eosinophils, mucus hyperplasia, mastocytosis, AHR, and increased expression of other Th2 cytokines and IgE (19). IL-9 blockade inhibits pulmonary eosinophilia, mucus hypersecretion, and AHR after allergen challenge of sensitized mice. Asthmatic patients show increased expression of IL-9 and its receptor in the airways (19). Many of the effects of IL-9 in mice (eosinophilic inflammation and mucus hypersecretion) are mediated via the release of IL-13, whereas its effects on mast cell expansion and B cells seem to be direct (20). IL-9 plays an important role in differentiation and proliferation of mast cells and interacts synergistically with SCF.
Th1 and Tc1 cytokines. The transcription factor T-bet is crucial for Th1 cell differentiation and secretion of the Th1-type cytokine IFN-γ. Consistent with the prominent role of Th2 cells in asthma, T-bet expression is reduced in T cells from the airways of asthmatic patients compared with airway T cells from nonasthmatic patients (21). After phosphorylation, T-bet associates with and inhibits the function of GATA3 by preventing it from binding to its DNA target sequences (22). In turn, GATA3 inhibits the production of Th1-type cytokines by inhibiting STAT4, the main transcription factor activated by the T-bet–inducing cytokine IL-12 (23). Th1 cells are the prominent CD4+ T cells, and Tc1 cells the predominant CD8+ T cells expressed in COPD lungs (24), but their role in the pathogenesis of COPD is not yet certain.
IFN-γ is the predominant cytokine produced by Th1 and Tc1 cells and may play an important role in inflammation in individuals with COPD by inducing the release of chemokines. In contrast, it is usually found at reduced levels in individuals with asthma, although levels of IFN-γ are increased in patients with more severe disease and acute exacerbations (25). IFN-γ activates T-bet via STAT1, resulting in expression of genes encoding Th1 cytokines and suppression of genes encoding Th2 cytokines (26). IFN-γ also orchestrates the infiltration of Th1 and Tc1 cells in the lungs of individuals with COPD through the upregulation of the chemokine receptor CXCR3 on these cells and the release of the CXCR3-activating chemokines CCL9 (also known as Mig), CCL10 (also known as IP-10), and CCL11 (also known as I-TAC) (24). Consistent with this, there is an increase in the number of T cells secreting IFN-γ in the airways of patients with COPD (27).
Type I and type III IFNs. Type 1 IFNs (IFN-α and IFN-β) and type III IFNs (IFN-λ) play an important role in innate immunity against viral infections, but IFN-β and IFN-λ show reduced expression in epithelial cells of asthmatic patients and are associated with increased rhinovirus replication, which may predispose these patients to viral exacerbations of asthma (28, 29). The molecular mechanism for these defects in innate immunity is not yet understood. Low-dose IFN-α seems to give marked benefit in patients with severe corticosteroid-resistant asthma but again the mechanism is unknown (30).
IL-12 and related cytokines. IL-12 plays an important role in differentiating and activating Th1 cells and is produced by activated macrophages, DCs, and airway epithelial cells (31). IL-12 induces T cells to release IFN-γ, which regulates the expression of IL-12Rβ2 and so maintains the differentiation of Th1 cells, whereas IL-4 suppresses IL-12Rβ2 expression and thus antagonizes Th1 cell differentiation. IL-12 levels released from whole-blood cells are lower in asthmatic patients, indicating a possible reduction in IL-12 secretion (32). In patients with mild asthma, recombinant IL-12 causes a progressive fall in circulating eosinophils but no reduction in allergen response or AHR, as with mepolizumab (the humanized blocking antibody specific for IL-5) (33). IL-12 is a heterodimer comprising p40 and p35 subunit; the p40 subunit is also a component of IL-23. The p40 subunit can also homodimerize to form IL-12p80, and both monomeric p40 and IL-12p80 can act as functional antagonists of IL-12 and IL-23 by binding to IL-12Rβ1 (34). However, they can also have proinflammatory effects through activating IL-12Rβ1, resulting in effects such as macrophage chemoattraction (34). Most of the effects of IL-12 are mediated via activation of STAT4, which is phosphorylated in the airways and BAL fluid lymphocytes of patients with COPD (27).
Originally described as IFN-γ–releasing factor, IL-18 has a mechanism of action different from that of IL-12 and may enhance Th1 responses independently of IL-12 (35). IL-12 and IL-18 appear to have a synergistic effect on the induction of IFN-γ release and the inhibition of IL-4–dependent IgE production and AHR. In individuals with COPD, IL-18 expression is increased in alveolar macrophages and CD8+ T cells in the airways and is correlated with disease severity (36).
IL-27 is a member of the IL-12 family that promotes Th1 cell differentiation through a STAT1-dependent mechanism independently of IL-12 (37). It is produced by activated APCs and enhances Th1 function by downregulating GATA3 expression and upregulating T-bet expression, thereby favoring the production Th1-type cytokines, which then act to further inhibit GATA3 expression (38). The role of IL-27 in asthma and COPD remains to be determined.
Th17 cytokines. Th17 cells are a subset of CD4+ T cells that play an important role in inflammatory diseases and are regulated by the transcription factor retinoic acid orphan receptor-γt (RORγt) (39). IL-6, IL-1β, TGF-β, and IL-23 are all involved in the differentiation of human Th17 cells (39, 40). Little is known about the role of Th17 cells in either asthma or COPD, but levels of IL-17A (the predominant product of Th17 cells) are increased in the sputum of individuals with asthma (41) and Th17 cells are increased in the airways of asthmatic subjects (42). IL-17A and the closely related IL-17F are linked to neutrophil-mediated inflammation by induction of the release of the neutrophil chemoattractants CXCL1 and CXCL8 from airway epithelial cells and airway smooth muscle cells (43) and thereby may play a role in the neutrophilic inflammation of severe asthma and COPD (44). IL-17 also increases the expression of mucin-encoding genes (MUC5AC and MUC5B) in human airway epithelial cells (45). However, the functional role of IL-17 in asthma is unclear, as it seems to be involved in allergic sensitization of animal models but to inhibit eosinophilic inflammation in sensitized animals (44).
Th17 cells also produce IL-21, which is important for the differentiation of these cells and thus acts as a positive autoregulatory factor (46). It also inhibits expression of the forkhead transcription factor forkhead box P3 (FOXP3) and thereby the development of Tregs (46). IL-22 is also released by Th17 cells and stimulates the production of IL-10 and acute-phase proteins. More work is needed to understand the role and regulation of Th17 cells in asthma and COPD, as they may provide important new targets for future therapy.
IL-25 (also known as IL-17E), another member of the IL-17 superfamily, is produced by Th2 cells, mast cells, and epithelial cells. IL-25 induces the expression of IL-4, IL-5, and IL-13, resulting in inflammation mediated by eosinophils, increased IgE production, and AHR in mice (47). It also enhances Th2 cytokine secretion from human Th2 cells (48). A blocking antibody specific for IL-25 inhibits the development of AHR in response to allergens in mice and is in clinical development for asthma (49).