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The Proceedings of the American Thoracic Society 1:222-230 (2004)
© 2004 The American Thoracic Society

Glucocorticoids Suppress Inflammation but Spare Innate Immune Responses in Airway Epithelium

Robert P. Schleimer

Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Robert P. Schleimer, Ph.D., Northwestern University Feinberg School of Medicine, Division of Allergy-Immunology, 240 East Huron Street, Rm. 2318, Chicago, IL 60611. E-mail: rpschleimer{at}northwestern.edu


   ABSTRACT
TOP
 ABSTRACT
EPITHELIAL ACTIVATION
 THE INFLUENCE OF GLUCOCORTICOIDS...
 EPITHELIUM AS A SENTINEL...
 THE INFLUENCE OF GLUCOCORTICOIDS...
 REFERENCES
 
Epithelial cells produce molecules that alter the growth and differentiation of mesenchymal cells, trigger the adhesion to endothelial cells and recruitment of inflammatory leukocytes, and regulate the activation of resident and infiltrating inflammatory cells. Recently, it has become clear that the airway epithelium also participates in innate immune responses. Accumulating evidence suggests that epithelial products such as complement, collectins, lysozyme, lactoferrin, secretory leukocyte protease inhibitor, and defensins can lead to localized destruction of microorganisms. While suppressing systemic adaptive immune responses, glucocorticoids exert little or no inhibitory effect on the ability of the epithelium to express these antimicrobial substances and, in some cases, may even elevate their production. Inhaled glucocorticoids generally profoundly inhibit epithelial cell expression of genes of inflammation, including chemokines, cytokines, and enzymes. Glucocorticoids may enhance the sensitivity of the epithelial surface to Toll-like receptor ligands, and they have been found to induce the expression of surfactant proteins A and D in several in vitro and in vivo model systems. Supporting the concept that glucocorticoids enhance innate immunity while suppressing adaptive immunity, these drugs enhance the survival and/or function of neutrophils and alveolar macrophages but induce the apoptosis of airway dendritic cells.

Key Words: adaptive immunity • allergic bronchopulmonary aspergillosis • asthma • chronic obstructive pulmonary disease • chronic rhinosinusitis

One of the common manifestations of asthma and chronic obstructive pulmonary disease (COPD) is epithelial activation. The respiratory mucosae are exposed to the primary causes of asthma and COPD, namely inhaled allergens and noxious materials contained in cigarette smoke. It is now clear that exacerbations of asthma and COPD are often triggered by infections of the respiratory tract. One theme of this review is that epithelial cells play a sentinel role in host responses to inhaled particles, allergens, and pathogens. Epithelial responses may be important in protective immunity as well as in disease pathogenesis. Another theme of this review is that glucocorticoids prevent the inflammation associated with exacerbations of asthma and COPD by microorganisms without disabling protective immunity. Targeting of inflammation in the context of intact immunity is a characteristic of glucocorticoids that is likely to have evolved to protect the body from life-threatening systemic inflammation without inducing susceptibility to pathogenic microorganisms. Some of the research discussed in this review has been published in abstract form.


   EPITHELIAL ACTIVATION
TOP
 ABSTRACT
 EPITHELIAL ACTIVATION
THE INFLUENCE OF GLUCOCORTICOIDS...
 EPITHELIUM AS A SENTINEL...
 THE INFLUENCE OF GLUCOCORTICOIDS...
 REFERENCES
 
Epithelial Responses
Activation of the epithelium has been observed in both asthma and COPD. Although the stimuli responsible and the mechanisms are likely to be largely distinct, several common characteristics are observed. Epithelial activation and epithelial responses are likely to be diverse, reflecting location (e.g., central vs. peripheral airways) but are discussed in general terms here. Epithelial damage, goblet cell differentiation, and increased mucus formation are features of both diseases. The recruitment of inflammatory cells observed in these diseases is suspected to be partly mediated by epithelial chemokine production. The primary chemokines produced are distinct (e.g., macrophage-derived chemokine, thymus- and activation-regulated chemokine, and eotaxins in asthma; interferon-{gamma}-inducible 10-kd protein [IP-10], interleukin [IL]-8, and the monokine induced by IFN-{gamma} [Mig] in COPD), resulting in distinct inflammatory cell infiltrates (CD4 type 2 T-helper [Th2] lymphocytes, eosinophils, and basophils in asthma; CD8 Th1 lymphocytes and neutrophils in COPD). Several transcription factors have been found to be activated and/or elevated in epithelium, including Fos, nuclear factor (NF)-{kappa}B, signal transduction–activated transcription factors 1 and 6, and Smad7, among others (1–8). A role of epithelium in remodeling has been proposed but is not clearly established in either disease.

Interactions between Epithelial Cells and Cells of the Immune System
Work from several laboratories demonstrates that asthma and COPD are characterized by infiltration of the airways with large numbers of activated lymphocytes that are important in initiation and perpetuation of airway inflammation (see articles by Jeffery and by Chanez and colleagues in this issue). Epithelial cells are exquisitely sensitive to cytokines produced by differentiated Th1 and Th2 lymphocytes, and the pattern of chemokines produced by epithelium depends on whether the primary activating cytokine profile is IFN-{gamma} or IL-4 and IL-13. Figure 1 illustrates IL-4–mediated and IL-13–mediated activation of epithelial expression of chemokines oriented toward recruitment of Th2 cells, eosinophils, and basophils. When the response is Th1-driven, IFN-{gamma} leads to epithelial expression of IP-10, IL-8, Mig, and growth-related oncogene-{alpha}, which recruit Th1 cells and neutrophils. It has been shown that adoptive transfer of Th1 cells produces a neutrophilic airway infiltrate, whereas transfer of Th2 cells produces an eosinophilic infiltrate (9). Although Th2 cells appear to be superior as inducers of goblet cell hyperplasia, Th1 cells are also capable of triggering this epithelial response (10). Although the local factors that sustain and regulate the state of activation of lymphocytes that infiltrate airways are incompletely known, it is now clear that epithelial cells may play a role (11–13).



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  		Figure 1. Inhibition of the recruitment of lymphocytes, eosinophils, and basophils by glucocorticoids is mediated in part by inhibition of the production of epithelium-derived chemokines (shown as GC in the box). TARC indicates thymus- and activation-regulated chemokine; MDC, macrophage-derived chemokine; MCP, monocyte chemoattractant protein; CCR, chemokine receptor.

 
Activation of lymphocytes occurs in lymph nodes draining a particular region of the body. Airway dendritic cells carry antigen to local lymph nodes, where they are presented in the context of major histocompatibility complex (MHC) class II and important costimulatory molecules. These molecules include the classical costimulators B7.1 and B7.2, as well as numerous homologs of these molecules, including B7-H1, B7-H2, B7-H3, B7-H4, and B7-DC. Recent studies of airway epithelial cells using both reverse transcriptase polymerase chain reaction (PCR) and flow cytometry have found that both cultured airway epithelial cells and cells in situ express minimal B7.1 and B7.2 and high constitutive levels of B7-H1, B7-H2, and B7-H3, with lower levels of B7-DC (12). Levels of expression of B7-H1 and B7-DC were dramatically increased by exposure to selected cytokines (14).

Although the significance of B7 homolog expression on airway epithelial cells is not established, it has been hypothesized that the expression of B7-H1, B7-H2, B7-H3, and B7-DC by airway epithelium may play an important role in maintaining or regulating the activation of antigen-specific lymphocytes that have migrated into the airways. In support of this concept, it is noteworthy that epithelial cells have many of the cell surface molecules associated with antigen presentation, including MHC class I and class II molecules and CD40 (15–18). Intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 are expressed on epithelial cells and could serve as ligands for leukocyte function-associated molecule-1 and {alpha}4 integrins expressed by T cells (19). Unlike peripheral blood T cells, long-lived intraepithelial T cells express {alpha}Eß7 integrin (CD103), a potential ligand for epithelial E-cadherin, suggesting that this molecule may help retain T cells in the mucosa (15, 20). Substantial numbers of T cells are found in association with epithelium in both the respiratory and gastrointestinal systems (15, 20). Mucosal inflammation is a hallmark of both asthma and COPD, and both of these diseases are characterized by activation of T cells and epithelial cells (1–7). The interactions between airway epithelial cells and T cells are likely to be important in the pathogenesis of asthma and COPD.


   THE INFLUENCE OF GLUCOCORTICOIDS ON ADAPTIVE IMMUNITY
TOP
 ABSTRACT
 EPITHELIAL ACTIVATION
 THE INFLUENCE OF GLUCOCORTICOIDS...
EPITHELIUM AS A SENTINEL...
 THE INFLUENCE OF GLUCOCORTICOIDS...
 REFERENCES
 
Glucocorticoids are a mainstay in the treatment of diseases characterized by airway inflammation, including asthma, COPD, chronic rhinosinusitis, and allergic bronchopulmonary aspergillosis. Their success directly reflects their ability to inhibit the recruitment and activation of inflammatory cells (Figure 1). The mechanism by which glucocorticoids exert this effect has been a subject of investigation for more than 50 years and has been reviewed extensively elsewhere (8). Epithelial cells are likely to be important effectors of the recruitment of lymphocytes and granulocytes by virtue of the production of chemokines and growth factors, and epithelial cells are clearly a target of the action of inhaled corticosteroids (ICSs) (21–24). As shown in Figure 1, the production of chemokines by epithelial cells is generally profoundly inhibited by glucocorticoids both in vivo and in vitro (21–24). This will have the effect of both reducing the total number of inflammatory cells that infiltrate the airways and diminishing the propensity of infiltrating cells to localize in the mucosal surface. As mentioned above, recent studies demonstrate that epithelial cells express inducible B7 homologs, including B7-H1 and B7-DC. The induction of these molecules is profoundly suppressed by treatment with glucocorticoids in cultured airway epithelial cells (14). Whether these molecules activate or suppress lymphocytes in the airways is still unknown. Regulation of the expression of B7 homologs in peripheral tissues such as epithelium by glucocorticoids is likely to indirectly influence the longevity and state of activation of infiltrating lymphocytes.


   EPITHELIUM AS A SENTINEL CELL TYPE IN INNATE IMMUNITY
TOP
 ABSTRACT
 EPITHELIAL ACTIVATION
 THE INFLUENCE OF GLUCOCORTICOIDS...
 EPITHELIUM AS A SENTINEL...
THE INFLUENCE OF GLUCOCORTICOIDS...
 REFERENCES
 
Because the respiratory mucosae are exposed to airborne particles, it is not surprising that epithelial cells also serve as a portal of entry and transmission for pathogenic microorganisms. Epithelial cells are the primary cell type infected by numerous respiratory viruses, and the mucosal surface is frequently the site of growth of bacteria and fungi. It is now clear that exacerbations of inflammatory diseases in the airways, including asthma, COPD, chronic rhinosinusitis, and allergic bronchopulmonary aspergillosis, are usually triggered by infections of the respiratory tract by viruses (e.g., rhinovirus), bacteria, and fungi.

In the past few years, studies from several groups have demonstrated that epithelial cells express receptors for pathogens and other noxious stimuli and exert a spectrum of innate immune responses (25). In the process of host resistance to such stimuli, epithelial cells serve barrier functions, are involved in removal of particulates, and initiate the recruitment of inflammatory cells to the airways. They also produce a host of antimicrobial products, including lysozyme, lactoferrin, cathelicidins, defensins, surfactants, and complement proteins.

Innate immune responses involve inherited pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMP) on pathogenic microorganisms (26). Pattern recognition receptors are encoded in the germ line and trigger responses to activation within minutes. PAMP are generally produced only by pathogens, are essential for the survival of the microorganism, and are invariant structures that are broadly expressed among pathogenic organisms. Examples of substances which contain PAMP include endotoxins, flagellin, lipopeptides, and double-stranded RNA (dsRNA). The pattern recognition receptors that recognize PAMP are generally involved in signaling of host cell activation or initiate the destruction of microorganisms either by promoting endocytosis or by direct toxicity to the pathogen.

Toll-Like Receptors
Epithelial cells express Toll-like receptors (TLRs) that can trigger epithelial activation through NF-{kappa}B and other signaling molecules in response to pathogens. TLRs can also be activated by host-derived molecules such as heat shock proteins and membrane lipids that are produced as a result of tissue damage, such as may occur with lung exposure to smoke (27–29). Ten distinct TLRs that recognize PAMP have been identified, each of which has extracellular leucine-rich domains, a transmembrane domain, and a signaling intracellular domain. Individual TLRs recognize distinct agonists (e.g., TLR-2 and TLR-4 recognize endotoxin and/or lipoproteins, TLR-9 recognizes CpG-containing DNA, TLR-3 recognizes dsRNA, and TLR-5 recognizes flagellin) (30, 31). Signaling through TLRs rapidly activates the expression of a host of cytokines, chemokines, hematopoietic factors, acute-phase proteins, and antimicrobial factors via intracytoplasmic domains resembling that of the IL-1 receptor (referred to as TIR domains), which initiate activation of kinase cascades. All TLRs activate NF-{kappa}B through MyD88 (a TIR domain–containing adaptor protein), IL-1 receptor–associated kinase, and tumor necrosis factor (TNF) receptor–associated factor-6 (30, 31), but MyD88-independent pathways of activation also exist (32, 33). The findings that TLRs can form heterodimers and the fact that at least 5 or 6 adaptor proteins exist suggest that TLR signaling is very diverse and likely to have great pathogen specificity.

Although it has been known for some time that epithelial cells are activated by various microorganisms and their products, especially lipopolysaccharide (LPS), there is relatively little published regarding epithelial cell expression of members of the TLR family. Cario and Podolski (35) have demonstrated that intestinal epithelial cells express TLR-2, TLR-3, TLR-4, and TLR-5. Interestingly, it has been demonstrated that TLRs are expressed on the basal side of intestinal epithelial cells and that triggering by intraluminal bacterial products may therefore require a breach of the epithelial barrier (35, 36). Studies by Song and coworkers have demonstrated fully functional expression of CD14 and TLR-4 on human corneal epithelial cells and keratinocytes (37). A recent study by Shuto and colleagues has demonstrated that TLR-2 expression on airway epithelium is elevated in otitis media (38). Less research has been performed on the expression and function of TLRs on human airway epithelial cells. Diamond and coworkers have demonstrated expression of TLR-2 and TLR-4 on airway epithelial cells and have shown that agonist (e.g., LPS) results in production of ß-defensins and other products (25).

It is reasonable to hypothesize that TLRs expressed on the airway epithelium play a role in the host response to pathogens and irritants. In a recent screen using TaqMan real-time PCR for all 10 known TLRs on primary and BEAS-2B airway epithelial cells, we detected mRNA for all 10 TLRs (39, 40). Notably expressed in cultured airway epithelial cells were TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, and TLR-10. Airway epithelial cells responded to a variety of TLR agonists, including LPS (recognized by TLR-4), zymosan (TLR-2), flagellin (TLR-5), and dsRNA (TLR-3), as tested in microarrays for NF-{kappa}B–related genes, chemokines, and chemokine receptors (GEArray). Although several genes were induced by LPS, zymosan, and flagellin, the most potent stimulus was dsRNA. Induced genes included chemokines, signaling molecules, several different TLRs, the acute-phase protein serum amyloid A (SAA), complement protein C3, and factor B from the alternative pathway of complement activation (discussed in more detail below). Taken together, these results indicate that airway epithelial cells express functional TLRs that enable the cells to respond directly to a variety of entities that contain PAMPs. The role that epithelial TLRs play in inflammation and disease exacerbation is worthy of future study.

The importance of the adrenal gland in stress responses and immunity to bacteria has been known for nearly a century; adrenalectomized animals are killed by doses of bacteria several logs less than those required to kill normal animals (41). An important action of glucocorticoids is the suppression of the release of cytokines that can cause systemic disease, such as TNF-{alpha}, IL-1, IL-12, etc. Glucocorticoids can suppress the release of these and other cytokines through signaling mechanisms that are well described elsewhere in this supplement (see the articles by Necela and Cidlowski, Adcock, and Stellato). With respect to TLR expression, recent studies by Silverstein and Johnson (41) and by Imasato and colleagues (42) surprisingly indicate that glucocorticoids could enhance epithelial expression of TLR-2 on cultured cells by nontypeable Haemophilus influenzae through activation of TLR-2 itself. Inhibition of p38 MAP kinase pathways with either specific inhibitors or glucocorticoids potentiated this response (38, 42). This result has recently been confirmed by Homma and coworkers (43), and suggests that glucocorticoids may enhance the sensitivity of the epithelial surface to TLR ligands in some cases.

Antimicrobial Responses
Inhaled glucocorticoids usually exert their anti-inflammatory effects in patients without causing outward signs of impairment of immunity (with the obvious exception of thrush, which occurs in the area consistently exposed to the greatest concentration of drug). In fact, it is notable that exacerbations of asthma, chronic rhinosinusitis, and acute bronchopulmonary aspergillosis, all of which are thought to be induced by pathogenic microorganisms, are regularly treated with good results using glucocorticoids. One key to this desirable profile of glucocorticoids may be that they fail to inhibit the expression of most epithelial cell genes involved in innate immunity (e.g., TLRs, surfactant proteins of the collectin family, complement and acute-phase proteins, etc). In contrast, glucocorticoids consistently inhibit epithelial cell expression of genes of inflammation (e.g., chemokines, cytokines, and enzymes) (Figure 2).




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  		Figure 2. (A) Airway epithelial cells express several classes of molecules involved in inflammation and host defense. Most of these are expressed at higher levels after exposure to stimuli that activate epithelial Toll-like receptors (TLRs). (B) In general, glucocorticoids (GCs) suppress the expression of mediators of inflammation (arrows shown on the basal side) but do not suppress, or in some cases enhance, innate immune effectors (arrows shown on the luminal side). GM-CSF = granulocyte macrophage colony-stimulating factor; iNOS = inducible nitric oxide synthase; COX-2 = cyclooxygenase-2.

 
The ability of epithelial fluids (e.g., tears, nasal lining fluid, sputum, etc.) to kill microorganisms has been known since Alexander Fleming discovered this property and identified lysozyme (44). It is now known that several major antimicrobial components are present in airway lining fluid, including lysozyme, lactoferrin, soluble leukocyte protease inhibitor (SLPI), and surfactant proteins A and D (45, 46). Also found in airways are defensins, including the classical {alpha}-defensins, produced to a great extent by granulocytes, and the ß-defensins (HBD 1 to 3), which are produced by epithelial cells (47, 48). HBD-2 is more potent in killing bacteria than HBD-1, and all the defensins display reduced activity in high-salt medium, a characteristic that may reduce their effectiveness in cystic fibrosis (49, 50). HBD-2 is induced in vitro by LPS and in vivo in patients with cystic fibrosis or interstitial lung disease, whereas ile HBD-1 is constitutively expressed (49, 50).

Unlike most of the antimicrobial products produced by epithelial cells, glucocorticoids have been reported to inhibit the release of HBD-2 stimulated by LPS in an airway cell line (51). Defensins display many properties of inflammatory mediators, and suppression of their expression by glucocorticoids may inhibit inflammation. For example, epithelial cells respond to defensins by producing a variety of chemokines and cytokines; this response is inhibited by glucocorticoids (52). Relatively little is published in the recent literature on the effects of glucocorticoids on the expression of lysozyme, lactoferrin, and SLPI. Ali and coworkers found that dexamethasone had no effect on spontaneous release of lysozyme and lactoferrin by human nasal explants in vitro (53). In contrast, Roca-Ferrer and associates found a modest (30–40%) inhibition of spontaneous lactoferrin secretion from cultured nasal or bronchial mucosa (54). In a study of patients with asthma and/or COPD, however, Schoonbrood and colleagues found that 4 weeks of treatment with an ICS led to increased median levels of sputum lactoferrin (55). Although the increase was not significant, there was no evidence that the ICS reduced lactoferrin levels (55). Studies of SLPI have found either no effect or increased levels of SLPI after treatment with an ICS (56, 57). In vitro studies have shown either no effect or a profound enhancement of SLPI expression when epithelial cells are stimulated with glucocorticoids (58, 59). Defensins also activate epithelial cells to express SLPI, and this response is not inhibited by glucocorticoids (58). SLPI has recently been reported to exert antimicrobial actions similar to those of lysozyme and lactoferrin, in addition to its ability to inhibit proteases (45). Taken together, these results suggest that glucocorticoids exert little or no inhibitory effect on the ability of the epithelium to express the primary constitutive antimicrobial substances lysozyme, lactoferrin, and SLPI. In some cases, glucocorticoids may elevate production of these substances.

Collectins and Surfactants
Of particular relevance to the role of epithelium in innate immunity are the collectins, which are pattern recognition molecules characterized by a collagenous domain linked to a calcium-dependent lectin domain (60). Collectins of note include mannose binding lectin and surfactant proteins (SP)-A and SP-D. Although not collectins, two other surfactant proteins, SP-B and SP-C, are also discussed here because their expression is modified in a meaningful way by glucocorticoids.

Pulmonary surfactant plays several important roles in the lung, including maintenance of airway surface tension, prevention of airway and alveolar collapse, and innate immune responses (60). Glucocorticoids increase disaturated phosphatidylcholine, a surfactant lipid, by inducing enzymes involved in its synthesis, including CTP: phosphocholine cytidylyltransferase and fatty acid synthase (61). Two surfactant proteins, SP-B and SP-C, are hydrophobic proteins that interact with surfactant lipids to reduce airway surface tension. An insufficient quantity of surfactant lipids, SP-B, and SP-C in the lungs of infants is partly responsible for respiratory distress syndrome. Glucocorticoids effectively induce expression of phospholipids as well as SP-B and SP-C, both of which contain a glucocorticoid response element in their promoter, by alveolar type II cells and airway Clara cells (62, 63).

Surfactant protein A and SP-D are members of the collectin family and play a direct role in host defense (64–66). These proteins are multimeric and bind to a diverse array of microorganisms via their lectin domains, which recognize bacterial and viral oligosaccharides as well as lipid-containing structures, including LPS (60, 64–66). Numerous in vitro studies have demonstrated that SP-A and SP-D are capable of agglutination of bacteria and fungi as well as opsonization. A recent study by Wu and colleagues has demonstrated that SP-A and SP-D can directly cause bacterial lysis by permeabilizing membranes (67). Mice deficient in SP-A exhibit reduced clearance of bacteria, viruses, and fungi, whereas mice deficient in SP-D spontaneously develop emphysema (65). Reduced levels of SP-A and SP-D are observed in several lung diseases, including cystic fibrosis, respiratory syncytial virus infection, lung damage syndromes, and adult respiratory distress syndrome, despite the observation that the TLR-4 ligand LPS induces expression of surfactant proteins (68, 69). Deficiency of SP-A and SP-D, either in knockout mice or in patients with early cystic fibrosis, is associated with increased airway inflammation (70–72).

Glucocorticoids have been found to induce the expression of SP-A and SP-D in several in vitro and in vivo model systems. Treatment of rats with dexamethasone led to a twofold increase in total lung SP-A, regardless of the age of the animal (73). Endogenous glucocorticoids appear to be essential in production of surfactant proteins; knockout of 11ß-hydroxysteroid dehydrogenase type I, which is important for local activation of endogenous glucocorticoid, led to depletion of lung surfactant (74). Maternal treatment with dexamethasone led to increases in SP-A, SP-B, and SP-C in newborn rats (75). Several different laboratories have demonstrated that glucocorticoids induce SP-A expression in explant culture systems using lung tissue derived from a variety of species, including humans (76–78). In these systems, SP-A is consistently induced by low concentrations of glucocorticoids, whereas prolonged exposure to high concentrations can lead to inhibition of SP-A expression (76–78). The inhibitory effect of high concentrations of glucocorticoid on SP-A expression results in part from post-transcriptional effects (i.e., decreased mRNA stability) dependent on the 3'UTR of the SP-A gene (79). More recently, techniques have been developed to culture type II alveolar cells that produce surfactant proteins in vitro. Glucocorticoids and cyclic adenosine monophosphate are important ingredients in the culture medium used for the growth and surfactant expression of these cells (80, 81). One of the important endogenous inducers of surfactant expression is keratinocyte growth factor, a potent surfactant stimulus in vitro (81). Glucocorticoids act synergistically with keratinocyte growth factor to induce SP-A, SP-B, and SP-C by a mechanism that is in part post-transcriptional (81). Studies of SP-D have yielded results similar to those of other surfactants. Glucocorticoids increase the expression of SP-D mRNA and protein both in vitro and in vivo. The most remarkable effect is an acceleration of expression of SP-D during fetal lung development (61, 82–84).

Mannose-binding lectin (MBL), a member of the collectin family, is important in innate immune responses by virtue of its ability to bind to bacteria and viruses expressing surface mannose or n-acetyl glucosamine residues. The complex of MBL and its associated serine proteases is structurally and functionally related to the complement protein complex C1qrs and can bind directly to bacteria and initiate complement-mediated lysis and/or opsonization (28, 85, 86). Deficiencies of MBL are relatively common and result from variants in either the promoter or the coding region (86). Reduced MBL is associated with susceptibility to infection to numerous pathogens. With respect to the lungs, MBL deficiency is associated with a twofold greater susceptibility to bacterial and viral infections (87, 88). In cystic fibrosis, significantly lower lung function is observed in MBL-deficient patients, and the median survival is 25 years compared with 34 years for patients with normal levels of MBL (89). In COPD, low MBL levels are associated with exacerbations (odds ratio of 4.9) but not with susceptibility (90). The effects of glucocorticoids on MBL have not been extensively evaluated. Levels of MBL in bronchoalveolar lavage fluid and sputum samples are low, and it has been proposed that the primary collectins in the airways are SP-A and SP-D. However, the strong effect of MBL deficiency on susceptibility to respiratory infections and exacerbations of COPD suggests that it plays an important role in the lung. It is unknown whether MBL can be produced locally in the airways. Low levels of MBL mRNA have been detected in sinonasal surgical samples, suggesting that local production may sometimes occur in the airways (91). Interestingly, glucocorticoids induce MBL in hepatocytes (92). If the effect of glucocorticoids on MBL resembles their effect on other complement proteins or collectins, little effect or enhanced expression may be anticipated, with the exception of indirect reductions of tissue levels secondary to inhibition of vascular leak.

Complement and Acute-Phase Proteins
Several molecules in the complement cascade have the capacity for direct pathogen recognition. When our studies of epithelial activation with TLR ligands revealed induction of these molecules, we reasoned that this may be part of a rapid host-protective response. Although complement and acute-phase proteins are mainly produced in the liver, several studies have demonstrated expression of complement proteins and/or receptors for complement by epithelial cells (93, 94). Relatively little information is available concerning regulation of epithelial complement protein expression, however. A study by Varsano and coworkers showed that epithelial cells produce increased levels of C3 after stimulation with cytokines (95). Walters and associates recently demonstrated that exposure to particulate matter induces airway hyperresponsiveness associated with epithelial localization of C3 in the airways (96). Whether the C3 in the epithelium was expressed by epithelial cells or was derived from plasma was not determined. Increased airway responsiveness was ablated, but inflammatory cell recruitment was not, in C3a receptor–deficient animals challenged with particulates or antigen (96, 97). Several groups have demonstrated that bronchoalveolar lavage fluids obtained from individuals with asthma and/or after segmental antigen challenge contain elevated levels of C3a, C5a, and other complement proteins (98–100). Drouin and colleagues demonstrated that mouse and human epithelial cells express receptors for C3a and C5a and that LPS challenge of mice leads to increased expression of C3a receptor but not C5a receptor on epithelial cells (101). Recent studies in our laboratories indicate that sinonasal tissue samples express modest levels of mRNA for proteins of the lectin-binding pathway (including the triggering molecule, MBL, and MBL-associated serine proteases 1 and 2), as well as robust levels of mRNA for C3 and the proteins in the alternative pathway tested to date (including factors B, P, H, and I) (91). We confirmed epithelial expression of C3 by immunohistochemistry in sinonasal samples, although the relationship of C3 expression to sinonasal disease activity has not been established. Cultured epithelial cells were found to express mRNA for the range of proteins of the alternative pathway of complement. These studies suggest that epithelial cells may produce the proteins necessary to arm the airways with complement proteins for purposes of host defense. These studies also suggest that expression of complement proteins by epithelial cells is dynamic and can be induced by TLRs as part of the innate immune response.

A few studies have assessed the influence of glucocorticoids on expression of complement genes in peripheral tissues. Muñoz-Cánoves and coworkers demonstrated that dexamethasone induced expression of factor H in endothelial cells (102). Similarly, Coulpier and colleagues found that high concentrations of glucocorticoids enhanced expression of C3 and factor B (103). Factor H expression was induced by glucocorticoids in synovial fibroblasts (104). We have recently observed that the robust induction of mRNA for factor B and factor H by the TLR-3 ligand dsRNA was not inhibited by fluticasone propionate (105).

SAA is another protein that was highly induced, more than threefold, in microarray studies of airway epithelial cells stimulated with the TLR-3 ligand dsRNA (39). Studies using TaqMan real-time PCR analysis revealed that stimulation of epithelial cells with dsRNA increased mRNA for SAA over 1,000-fold, and studies with a specific ELISA revealed a 20-fold increase in levels of SAA after stimulation with dsRNA. The potent glucocorticoid fluticasone propionate increased basal levels of SAA and did not inhibit the induction of SAA by dsRNA. There are four genes for SAA in humans: SAA1 and SAA2 are inducible acute-phase forms, SAA3 is a pseudogene, and SAA4 is a circulating, constitutive form (106, 107). Levels of SAA can be elevated as much as 1,000-fold in systemic inflammatory diseases and/or amyloidosis. Although SAA proteins are primarily produced in the liver, extrahepatic production has been reported in macrophages, endothelial cells, and other cell types in vivo or in vitro after stimulation with cytokines, including IL-1, TNF-{alpha}, or IL-6 (107). The relevance of inducible SAA expression by airway epithelial cells is uncertain. However, levels of SAA have been shown to correlate with poor prognosis in rheumatoid arthritis and atherosclerosis (108, 109). Circulating SAA and other acute-phase proteins have been found to be elevated in asthma and COPD (110, 111). It is notable that formyl peptide receptor–like 1, the low-affinity receptor for formyl-Met-Leu-Phe that is also a receptor for lipoxin A4, has been shown to mediate chemotactic and cytokine-inducing effects of SAA on neutrophils (112, 113). SAA has been shown to induce the release of matrix metalloproteinases in chondrocytes and is suspected of having a role in remodeling of the joint in rheumatoid arthritis (114). Confusion over the etiologic role of SAA in these diseases relates to the fact that SAA potentially has both positive and negative effects on immune and inflammatory responses (105, 107). Further studies are required to better understand the role that this protein plays in airway inflammation and remodeling induced by pathogens and allergens. Based on the hypotheses advanced in this review, it is reasonable to suggest that SAA may play an important role in innate immune responses.


   THE INFLUENCE OF GLUCOCORTICOIDS ON INNATE IMMUNITY
TOP
 ABSTRACT
 EPITHELIAL ACTIVATION
 THE INFLUENCE OF GLUCOCORTICOIDS...
 EPITHELIUM AS A SENTINEL...
 THE INFLUENCE OF GLUCOCORTICOIDS...
REFERENCES
 
The information in this review coalesces to give the view that glucocorticoids spare innate immune responses and can in some cases be documented to enhance the production of numerous effectors of innate immunity, including complement, collectins, acute-phase proteins, and SLPI. Of course, the ability of glucocorticoids to enhance production of complement and acute-phase proteins by the liver has been known for decades. However, it has recently been discovered that many of these proteins are produced locally and that glucocorticoids in many cases potentiate their production, which suggests that mobilization of glucocorticoids during infection, stress, or a fight-or-flight event may promote innate immunity both locally and systemically.

Supporting the concept that glucocorticoids enhance innate immunity, while suppressing adaptive immunity, is the influence of these drugs on the behavior of phagocytic cells. Macrophages and neutrophils are essential effector cells in innate immunity while dendritic cells are primarily cells that trigger adaptive immune responses. The influence of glucocorticoids on these cell types is summarized in Figure 3. Systemic glucocorticoids profoundly increase circulating neutrophil numbers (three- to fivefold) and have been shown to enhance the survival and function of neutrophils (8). The inhibitory effects of glucocorticoids on leukocyte recruitment are mediated at the level of the production of the chemoattractants, not at the level of the leukocyte response. If chemoattractants (e.g., C3a, C5a, SAA, etc.) can be generated in the presence of glucocorticoids, then neutrophils and other cells with appropriate receptors are free to migrate despite the presence of glucocorticoids. The phagocytic capacity of alveolar macrophages has been shown to be significantly potentiated by glucocorticoids, an effect that is appropriate in a situation where opsonin production is potentiated by glucocorticoids (i.e., increased C3b, SP-A, SP-D, and MBL) (115, 116). Finally, glucocorticoids have been shown to reduce DR+ human leukocyte antigen cells in the lungs and have recently been shown to induce widespread dendritic cell apoptosis (117). This action of glucocorticoids is likely to result in decreased T-cell activation in lymph nodes and may contribute to the well established ability of glucocorticoids to suppress the influx of T cells into the lungs.



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  		Figure 3. Effects of glucocorticoids (GCs) on phagocytic cells involved in innate and adaptive immunity. They enhance the survival and/or function of neutrophils and alveolar macrophages but induce the apoptosis of airway dendritic cells. PMN = polymorphonuclear neutrophil leukocytes.

 
The ability of glucocorticoids to reduce exacerbations of asthma, chronic rhinosinusitis, allergic bronchopulmonary aspergillosis, and other respiratory diseases may result not only from their well recognized ability to inhibit inflammation and restore tissue architecture, but also from their ability to facilitate innate immune responses in the airways that provide resistance to the pathogens that trigger disease exacerbations.


   ACKNOWLEDGMENTS
 
R.P.S. received consultancy money from GlaxoSmithKline (GSK) ($2,500 in 2002 and $2,500 in 2003) and from Aventis Pharmaceuticals ($3,000 in 2002 and $4,000 in 2003) and from Dynavax ($10,000 per year in 2001, 2002, and 2003) and received sponsored grants from GSK ($60,000 in 2002 and $48,000 in 2003).

The author thanks Ms. Bonnie Hebden and Ms. Margaret Mateja for their superb assistance in the preparation of this review.

(Received in original form February 18, 2004; accepted in final form August 3, 2004)


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