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The Contribution of the Airway Epithelial Cell to Host Defense.

Stanke F - Mediators Inflamm. (2015)

Bottom Line: The ability of an epithelial cell to initiate CFTR-mediated chloride and bicarbonate transport has been recognized early as a means to regulate the thickness of the epithelial lining fluid and recently as a means to regulate the pH, thereby determining critically whether or not host defense proteins such as mucins are able to fold appropriately.This paper summarizes functional data that describes the effect of cytokines, chemokines, infectious agents, and inflammatory conditions on the ion transport properties of the epithelial cell and relates these key properties to the molecular pathology of cystic fibrosis.Recent findings on the role of cystic fibrosis modifier genes that underscore the role of the epithelial ion transport in host defense and inflammation are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Hannover Medical School, Carl-Neuberg-Strasse, 30625 Hannover, Germany ; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover, Germany.

ABSTRACT
In the context of cystic fibrosis, the epithelial cell has been characterized in terms of its ion transport capabilities. The ability of an epithelial cell to initiate CFTR-mediated chloride and bicarbonate transport has been recognized early as a means to regulate the thickness of the epithelial lining fluid and recently as a means to regulate the pH, thereby determining critically whether or not host defense proteins such as mucins are able to fold appropriately. This review describes how the epithelial cell senses the presence of pathogens and inflammatory conditions, which, in turn, facilitates the activation of CFTR and thus directly promotes pathogens clearance and innate immune defense on the surface of the epithelial cell. This paper summarizes functional data that describes the effect of cytokines, chemokines, infectious agents, and inflammatory conditions on the ion transport properties of the epithelial cell and relates these key properties to the molecular pathology of cystic fibrosis. Recent findings on the role of cystic fibrosis modifier genes that underscore the role of the epithelial ion transport in host defense and inflammation are discussed.

No MeSH data available.


Related in: MedlinePlus

Association of TNFR1 variants with CF disease severity and manifestation of CFTR-mediated residual chloride secretion in respiratory tissue among F508del-CFTR homozygous CF patients. (a) Definition of TNFR1 variants. Two contrasting haplotypes, designated haplotype 1 and haplotype 2 within this figure, were described by typing the five markers rs4149576, D12S889, rs4149577, rs4149580, and rs4149581 among 101 families with a total of 171 F508del-CFTR homozygous CF patients [13]. Haplotypes were reconstructed using the software FAMHAP [14]. Association was judged by case-reference association whereby cases and references were defined based on the disease severity of the siblings (b) or the manifestation of a change in potential upon superfusion of the nasal epithelium with chloride-free solution and isoproterenol (c). All P values reported within this figure were calculated by FAMHAP and are corrected for sibling dependence and testing of multiple markers [14]. Please note that the case and control subpopulations compared within (b) and (c) were defined independently and were nonoverlapping (for details, please see [13]). Please also note that haplotype 2, depicted in green within this figure, is overrepresented among sib pairs with mild CF disease and among patients who display CFTR-mediated residual chloride secretion by NPD. As a causal interpretation, this might reflect the crosstalk between the cytokine pathway and the ion secretory properties of the epithelium [15–25], indicating that the mild TNFR1 haplotype 2 is more susceptible to translating the action of the host defense modifier gene TNFR1 into CFTR-mediated residual function. Alternatively, as CFTR-mediated residual chloride secretion causes a mild disease phenotype, the observed TNFR1 association with the manifestation of the basic defect in NPD might reflect an overrepresentation of mild modifier alleles among patients with residual CFTR-mediated chloride secretion, which is equivalent to a replication study with confirmatory outcome.
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fig1: Association of TNFR1 variants with CF disease severity and manifestation of CFTR-mediated residual chloride secretion in respiratory tissue among F508del-CFTR homozygous CF patients. (a) Definition of TNFR1 variants. Two contrasting haplotypes, designated haplotype 1 and haplotype 2 within this figure, were described by typing the five markers rs4149576, D12S889, rs4149577, rs4149580, and rs4149581 among 101 families with a total of 171 F508del-CFTR homozygous CF patients [13]. Haplotypes were reconstructed using the software FAMHAP [14]. Association was judged by case-reference association whereby cases and references were defined based on the disease severity of the siblings (b) or the manifestation of a change in potential upon superfusion of the nasal epithelium with chloride-free solution and isoproterenol (c). All P values reported within this figure were calculated by FAMHAP and are corrected for sibling dependence and testing of multiple markers [14]. Please note that the case and control subpopulations compared within (b) and (c) were defined independently and were nonoverlapping (for details, please see [13]). Please also note that haplotype 2, depicted in green within this figure, is overrepresented among sib pairs with mild CF disease and among patients who display CFTR-mediated residual chloride secretion by NPD. As a causal interpretation, this might reflect the crosstalk between the cytokine pathway and the ion secretory properties of the epithelium [15–25], indicating that the mild TNFR1 haplotype 2 is more susceptible to translating the action of the host defense modifier gene TNFR1 into CFTR-mediated residual function. Alternatively, as CFTR-mediated residual chloride secretion causes a mild disease phenotype, the observed TNFR1 association with the manifestation of the basic defect in NPD might reflect an overrepresentation of mild modifier alleles among patients with residual CFTR-mediated chloride secretion, which is equivalent to a replication study with confirmatory outcome.

Mentions: Modifier genes of cystic fibrosis disease severity have now been studied for a decade [31, 32]. Many studies are candidate genes based; that is, the investigators rely on a hypothesis of which of the 22.000 protein-coding human genes [33] is likely to influence CF disease. Several researchers have selected genes encoding for cytokines such as TNFA, IL1B, and TGFB1 as candidate genes because of their known role in infection, immunology, and inflammation [13, 34–38]. Among these immunologically relevant candidate genes, IL1B has been replicated in two truly independent studies [35, 39], albeit the molecular variant has not been mapped by the base yet. The cytokine receptors TNFR1 and IFNGR1 have been studied as modifier genes in European CF Twin and Sibling Study [13, 39, 40]. Until now, the CF basic defect that can be assessed by nasal potential difference measurement in vivo has only been used by the European CF Twin and Sibling Study for an association study. Strikingly, the TNFα receptor 1 gene TNFR1 was observed as a modifier of CF disease severity as well as of CFTR-mediated residual chloride secretion in the nasal epithelium, whereby the risk and the benign allele were identified consistently for both traits ([13, 40], Figure 1). Furthermore, several immunologically relevant genes were identified as modifiers of the CFTR-mediated basic defect ([13], Table 2). This observation parallels the aforementioned observed capabilities of cytokines to activate fluid secretion by airway epithelial cells in order to promote clearance: as functional experiments using human airway epithelial cell lines, primary airway epithelial cells, and animal models have demonstrated that cytokines can alter ion and fluid transport in the respiratory epithelium effectively [15–25], it must be expected that genetic variants in cytokines and their receptors show genetic association with the manifestation of the basic defect among cystic fibrosis patients [13].


The Contribution of the Airway Epithelial Cell to Host Defense.

Stanke F - Mediators Inflamm. (2015)

Association of TNFR1 variants with CF disease severity and manifestation of CFTR-mediated residual chloride secretion in respiratory tissue among F508del-CFTR homozygous CF patients. (a) Definition of TNFR1 variants. Two contrasting haplotypes, designated haplotype 1 and haplotype 2 within this figure, were described by typing the five markers rs4149576, D12S889, rs4149577, rs4149580, and rs4149581 among 101 families with a total of 171 F508del-CFTR homozygous CF patients [13]. Haplotypes were reconstructed using the software FAMHAP [14]. Association was judged by case-reference association whereby cases and references were defined based on the disease severity of the siblings (b) or the manifestation of a change in potential upon superfusion of the nasal epithelium with chloride-free solution and isoproterenol (c). All P values reported within this figure were calculated by FAMHAP and are corrected for sibling dependence and testing of multiple markers [14]. Please note that the case and control subpopulations compared within (b) and (c) were defined independently and were nonoverlapping (for details, please see [13]). Please also note that haplotype 2, depicted in green within this figure, is overrepresented among sib pairs with mild CF disease and among patients who display CFTR-mediated residual chloride secretion by NPD. As a causal interpretation, this might reflect the crosstalk between the cytokine pathway and the ion secretory properties of the epithelium [15–25], indicating that the mild TNFR1 haplotype 2 is more susceptible to translating the action of the host defense modifier gene TNFR1 into CFTR-mediated residual function. Alternatively, as CFTR-mediated residual chloride secretion causes a mild disease phenotype, the observed TNFR1 association with the manifestation of the basic defect in NPD might reflect an overrepresentation of mild modifier alleles among patients with residual CFTR-mediated chloride secretion, which is equivalent to a replication study with confirmatory outcome.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4491388&req=5

fig1: Association of TNFR1 variants with CF disease severity and manifestation of CFTR-mediated residual chloride secretion in respiratory tissue among F508del-CFTR homozygous CF patients. (a) Definition of TNFR1 variants. Two contrasting haplotypes, designated haplotype 1 and haplotype 2 within this figure, were described by typing the five markers rs4149576, D12S889, rs4149577, rs4149580, and rs4149581 among 101 families with a total of 171 F508del-CFTR homozygous CF patients [13]. Haplotypes were reconstructed using the software FAMHAP [14]. Association was judged by case-reference association whereby cases and references were defined based on the disease severity of the siblings (b) or the manifestation of a change in potential upon superfusion of the nasal epithelium with chloride-free solution and isoproterenol (c). All P values reported within this figure were calculated by FAMHAP and are corrected for sibling dependence and testing of multiple markers [14]. Please note that the case and control subpopulations compared within (b) and (c) were defined independently and were nonoverlapping (for details, please see [13]). Please also note that haplotype 2, depicted in green within this figure, is overrepresented among sib pairs with mild CF disease and among patients who display CFTR-mediated residual chloride secretion by NPD. As a causal interpretation, this might reflect the crosstalk between the cytokine pathway and the ion secretory properties of the epithelium [15–25], indicating that the mild TNFR1 haplotype 2 is more susceptible to translating the action of the host defense modifier gene TNFR1 into CFTR-mediated residual function. Alternatively, as CFTR-mediated residual chloride secretion causes a mild disease phenotype, the observed TNFR1 association with the manifestation of the basic defect in NPD might reflect an overrepresentation of mild modifier alleles among patients with residual CFTR-mediated chloride secretion, which is equivalent to a replication study with confirmatory outcome.
Mentions: Modifier genes of cystic fibrosis disease severity have now been studied for a decade [31, 32]. Many studies are candidate genes based; that is, the investigators rely on a hypothesis of which of the 22.000 protein-coding human genes [33] is likely to influence CF disease. Several researchers have selected genes encoding for cytokines such as TNFA, IL1B, and TGFB1 as candidate genes because of their known role in infection, immunology, and inflammation [13, 34–38]. Among these immunologically relevant candidate genes, IL1B has been replicated in two truly independent studies [35, 39], albeit the molecular variant has not been mapped by the base yet. The cytokine receptors TNFR1 and IFNGR1 have been studied as modifier genes in European CF Twin and Sibling Study [13, 39, 40]. Until now, the CF basic defect that can be assessed by nasal potential difference measurement in vivo has only been used by the European CF Twin and Sibling Study for an association study. Strikingly, the TNFα receptor 1 gene TNFR1 was observed as a modifier of CF disease severity as well as of CFTR-mediated residual chloride secretion in the nasal epithelium, whereby the risk and the benign allele were identified consistently for both traits ([13, 40], Figure 1). Furthermore, several immunologically relevant genes were identified as modifiers of the CFTR-mediated basic defect ([13], Table 2). This observation parallels the aforementioned observed capabilities of cytokines to activate fluid secretion by airway epithelial cells in order to promote clearance: as functional experiments using human airway epithelial cell lines, primary airway epithelial cells, and animal models have demonstrated that cytokines can alter ion and fluid transport in the respiratory epithelium effectively [15–25], it must be expected that genetic variants in cytokines and their receptors show genetic association with the manifestation of the basic defect among cystic fibrosis patients [13].

Bottom Line: The ability of an epithelial cell to initiate CFTR-mediated chloride and bicarbonate transport has been recognized early as a means to regulate the thickness of the epithelial lining fluid and recently as a means to regulate the pH, thereby determining critically whether or not host defense proteins such as mucins are able to fold appropriately.This paper summarizes functional data that describes the effect of cytokines, chemokines, infectious agents, and inflammatory conditions on the ion transport properties of the epithelial cell and relates these key properties to the molecular pathology of cystic fibrosis.Recent findings on the role of cystic fibrosis modifier genes that underscore the role of the epithelial ion transport in host defense and inflammation are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Hannover Medical School, Carl-Neuberg-Strasse, 30625 Hannover, Germany ; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover, Germany.

ABSTRACT
In the context of cystic fibrosis, the epithelial cell has been characterized in terms of its ion transport capabilities. The ability of an epithelial cell to initiate CFTR-mediated chloride and bicarbonate transport has been recognized early as a means to regulate the thickness of the epithelial lining fluid and recently as a means to regulate the pH, thereby determining critically whether or not host defense proteins such as mucins are able to fold appropriately. This review describes how the epithelial cell senses the presence of pathogens and inflammatory conditions, which, in turn, facilitates the activation of CFTR and thus directly promotes pathogens clearance and innate immune defense on the surface of the epithelial cell. This paper summarizes functional data that describes the effect of cytokines, chemokines, infectious agents, and inflammatory conditions on the ion transport properties of the epithelial cell and relates these key properties to the molecular pathology of cystic fibrosis. Recent findings on the role of cystic fibrosis modifier genes that underscore the role of the epithelial ion transport in host defense and inflammation are discussed.

No MeSH data available.


Related in: MedlinePlus