Biomedical subjects

Paul S Foster

Publications and source records attributed to Paul S Foster.

At least 37 records · Page 2Linked to original sources

PubMed2004

Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9).

Experimental analysis of allergic airway inflammation (AAI) in animals and humans is associated with coordinate gene induction. Using DNA microarray analysis, we have identified a large panel of AAI signature genes. Unexpectedly, the allergen-challenged lung (a T helper 2 microenvironment) was found to be associated with the expression of T helper 1-associated CXCR3 ligands, monokine induced by IFN-gamma (Mig), and IFN-gamma-inducible protein of 10 kDa (IP-10). Here we report that Mig functions as a negative regulator of murine eosinophils. Whereas Mig was not able to induce chemotaxis of eosinophils, pretreatment with Mig induced a dose-dependent inhibition of chemoattractant-induced eosinophil transmigration in vitro. Moreover, i.v. administration of low doses of Mig ( approximately 10-30 microg/kg) induced strong and specific dose-dependent inhibition of chemokine-, IL-13-, and allergen-induced eosinophil recruitment and, conversely, neutralization of Mig before allergen challenge increased airway eosinophilia. Importantly, Mig also inhibited a CCR3-mediated functional response in eosinophils. These results indicate that the ultimate distribution and function of inflammatory cells within the allergic lung is dictated by a balance between positively and negatively regulatory chemokines. The identification of a naturally occurring eosinophil inhibitory chemokine pathway in vivo provides a strategic basis for future therapeutic consideration.

Allergens↗

PubMed2004

Polymorphisms in IL-4R alpha correlate with airways hyperreactivity, eosinophilia, and Ym protein expression in allergic IL-13-/- mice.

The development of airways hyperreactivity in allergic IL-13(-/-) mice is controversial and appears to correlate with the number of times that the original 129 x C57BL/6 founder strain has been crossed to the BALB/c background. In this investigation, we compared allergic responses in founder IL-13(-/-) mice crossed for either 5 (N5) or 10 (N10) generations to BALB/c mice. Whereas allergic N5 IL-13(-/-) mice developed airways hyperreactivity, tissue eosinophilia, elevated IgE, and pulmonary expression of Ym proteins, these processes were attenuated in N5 IL-13(-/-) mice treated with an IL-4-neutralizing Ab, and in N10 IL-13(-/-) mice. These data showed that IL-4 was more effective in regulating allergic responses in N5 IL-13(-/-) mice than in N10 IL-13(-/-) mice. To elucidate the mechanism associated with these observations, we show by restriction and sequence analysis that N5 IL-13(-/-) mice express the C57BL/6 form of IL-4Ralpha and N10 IL-13(-/-) mice express the BALB/c form. Despite the near identical predicted molecular mass of these isoforms, IL-4Ralpha from N5 IL-13(-/-) mice migrates with a slower electrophoretic mobility than IL-4Ralpha from N10 IL-13(-/-) mice, suggesting more extensive posttranslational modification of the N5 form. The Thre(49)Ile polymorphism in the extracellular domain of BALB/c IL-4Ralpha has been demonstrated to disrupt N-linked glycosylation of Asn(47) and increase the dissociation rate of the IL-4Ralpha/IL-4 interaction. Collectively, these data show that polymorphisms in IL-4Ralpha, which have been shown to affect the interaction with IL-4, correlate with the ability of IL-4 to regulate allergic responses in IL-13(-/-) mice.

Adipokines↗

PubMed2004

Chemokines in eosinophil-associated gastrointestinal disorders.

Eosinophil-associated gastrointestinal disorders (EGDs) are characterized by a pronounced cellular inflammation. Recent clinical and experimental investigations have implicated a family of molecules known as chemokines in the regulation of leukocyte recruitment in these diseases. The underlying cellular and molecular mechanisms involved in chemokine-mediated cellular infiltration are largely unknown. In this review, we describe the role of CD4+ T cells and eosinophils in the clinical manifestations of EGDs and discuss the current understanding of the role of chemokines in the recruitment of these cells in the expression of diseases.

Animals↗

PubMed2004

The covariation of cortical electrical activity and cardiovascular responding.

Integrating findings from research concerning the cerebral and cardiovascular effects of increasing emotional intensity suggests that changes in functional cerebral system activation and changes in heart rate and blood pressure are related. Research has indicated that the left and right cerebral hemispheres are specialized for parasympathetic and sympathetic control of cardiovascular functioning. The present investigation sought to determine whether significant correlations existed between changes in the magnitude (microV) of alpha (8-13 Hz), low beta (13-21 Hz), and high beta (21-32 Hz) EEG activity at the frontal and temporal lobes and changes in heart rate as well as systolic and diastolic blood pressure. The results indicated that changes in the magnitude of each bandwidth analyzed were significantly correlated with changes in all three cardiovascular measures at several sites across the cerebral hemispheres, including the frontal and temporal lobes. The findings are discussed in terms of explaining the cardiovascular effects of increasing emotional intensity. Clinical implications of the findings are also discussed and suggestions for future research are provided.

Adolescent↗

PubMed2004

Use of the Calmset 3 biofeedback/relaxation system in the assessment and treatment of chronic nocturnal bruxism.

Biofeedback and nocturnal alarms using electromyographic (EMG) activity of the masseter muscles have often been used to treat nocturnal bruxism. However, although use of EMG activated nocturnal alarms has been successful, the clinical utility of the devices reported in the literature to date is questionable. For instance, many of the devices are cumbersome and specifically designed and constructed by the investigators. Hence, the purpose of the present investigation was to test the clinical utility of the Calmset (Thought Technology Limited, Montreal, Canada), a commercially available, user-friendly, compact, and portable EMG biofeedback instrument that may be used as an EMG activated nocturnal alarm. To meet this objective, the Calmset was used both to facilitate assessment and to treat an individual with chronic nocturnal bruxism. The results indicated that the patient exhibited fewer bruxing episodes following treatment and that treatment gains were maintained 6 months following termination of treatment. Advantages and disadvantages of using the Calmset are discussed.

Adult↗

PubMed2004

T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice.

BACKGROUND & AIMS: Eosinophil-associated gastrointestinal diseases are frequently associated with extraintestinal features, including bronchopulmonary manifestations. The factors predisposing to bronchial hyperresponsiveness in eosinophil-associated gastrointestinal diseases are unknown. To elucidate the mechanistic link between eosinophil-associated gastrointestinal diseases and bronchial hyperresponsiveness, we used murine models of eosinophil-associated gastrointestinal diseases and eotaxin-1/transgene-induced eosinophil-associated gastrointestinal diseases. METHODS: Mice were sensitized and orally challenged with ovalbumin-coated encapsulated particles to induce eosinophil-associated gastrointestinal disease, and bronchial responsiveness was examined. Furthermore, transgenic mice expressing eotaxin in the intestine (with the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in eosinophil-associated gastrointestinal disease-associated bronchial hyperresponsiveness. RESULTS: The induction of allergen-induced eosinophil-associated gastrointestinal disease was directly correlated with the development of bronchial hyperresponsiveness. The development of bronchial hyperresponsiveness in mice with allergen-induced eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal tract. Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote bronchial hyperresponsiveness. Bronchial hyperresponsiveness was shown to be directly linked to the aberrant CD4(+) T helper 2 lymphocyte production of interleukin-13. It is interesting to note that transgenic expression of eotaxin was linked with enhanced T helper 2 lymphocyte/cytokine synthesis (interleukin-4, -5, and -13) and the production of mucosal immunoglobulin G1 in the gastrointestinal lumen. We also showed that eotaxin treatment of CD4(+) T cells enhanced interleukin-13 production in vitro. CONCLUSIONS: These studies suggest that increased expression of eotaxin in the gastrointestinal compartment can lead to increased CD4(+) T cell-derived T helper 2 lymphocyte-cytokine production that drives aberrant immunophysiological responses in distant noninflamed mucosal tissue (the lung). These results provide a possible explanation for the altered lung function seen in some patients with inflammatory gastrointestinal disorders.

Animals↗

PubMed2004

Cerebral correlates of varying ages of emotional memories.

OBJECTIVE: The purpose of the present study was to investigate the cerebral correlates of varying ages of emotional memories using quantitative electroencephalography. BACKGROUND: Recollection of emotional memories has often been used as a method of inducing emotional arousal in studies seeking to investigate the cerebral correlates of emotional arousal. However, the specific effects of the ages of the memories recalled on resulting changes in cerebral activity have not been investigated. METHOD: A total of 16 female undergraduates were asked to recollect an angry memory while quantitative electroencephalography was recorded. Following recollection, they were further asked to indicate the age of the memory recalled. RESULTS: The results indicated that significant correlations existed between ages of angry memories and changes in the magnitude of low beta (13 to 21 Hz) and high beta (21 to 32 Hz) at the right frontal, left temporal, and bilateral parietal regions of the brain. CONCLUSIONS: The results support an integration of the spreading activation and parallel distributed processing models of memory in predicting the cerebral effects of varying ages of emotional memories. Further, given the present findings, it may be important for investigators to determine the ages of the memories recalled so as to control or otherwise account for the effects of this potentially confounding variable.

Adolescent↗

PubMed2003

Type 2 cytokines in the pathogenesis of sustained airway dysfunction and airway remodeling in mice.

The mechanisms underlying airway hyperresponsiveness remain unclear, although airway inflammation and remodeling likely play important roles. We have observed sustained airway hyperreactivity and airway remodeling occurring in mice after chronic allergen exposure and persisting beyond resolution of allergen-induced inflammation. The aim of this study was to delineate mechanisms involved in allergen-induced airway hyperreactivity and airway remodeling and to examine evidence for a causal association between airway remodeling and sustained airway hyperreactivity. Wild-type (WT) and interleukin (IL)-4-, IL-5-, and IL-13-deficient (-/-) mice were sensitized and studied 4 weeks after chronic allergen exposure. By measuring airway responsiveness and airway morphometry, we demonstrated that WT mice developed sustained airway hyperreactivity and aspects of airway remodeling after chronic allergen exposure. Both IL-4(-/-) and IL-13(-/-) mice were protected from developing sustained airway hyperreactivity and aspects of airway remodeling. In contrast, IL-5(-/-) mice developed sustained airway hyperreactivity and aspects of airway remodeling similar to that seen in WT mice. Our results confirm that IL-4 and IL-13, but not IL-5, are critical for the development of sustained airway hyperreactivity and airway remodeling after allergen exposure.

Analysis of Variance↗

PubMed2003

Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma.

Phosphodiesterase (PDE) inhibitors have potential as alternatives or adjuncts to glucocorticoid therapy in asthma. We compared roflumilast (a selective PDE4 inhibitor) with pentoxifylline (a nonselective inhibitor) and dexamethasone in ameliorating the lesions of chronic asthma in a mouse model. BALB/c mice sensitized to ovalbumin were chronically challenged with aerosolized antigen for 6 weeks. During weeks 5 and 6, groups of animals were treated with roflumilast or dexamethasone by daily gavage or with pentoxifylline by daily intraperitoneal injection. Airway hyper-reactivity (AHR) was evaluated by whole-body plethysmography and airway lesions by histomorphometry and immunohistochemistry. Compared with vehicle alone, treatment with roflumilast or dexamethasone significantly reduced accumulation of eosinophils and chronic inflammatory cells, subepithelial collagenization, and thickening of the airway epithelium. Dexamethasone also reduced goblet cell hyperplasia/metaplasia, subepithelial accumulation of transforming growth factor-beta1, and epithelial cytoplasmic immunoreactivity for nuclear factor-kappaB. Treatment with pentoxifylline inhibited only eosinophil recruitment and epithelial thickening. Roflumilast and dexamethasone slightly decreased AHR, whereas this was significantly reduced by pentoxifylline. Thus, in this model of chronic asthma, both roflumilast and dexamethasone were potent inhibitors of airway inflammation and remodeling. Roflumilast did not diminish accumulation of transforming growth factor-beta1, suggesting that it might affect remodeling by mechanisms distinct from glucocorticoids.

Aminopyridines↗

PubMed2003

A plant-based allergy vaccine suppresses experimental asthma via an IFN-gamma and CD4+CD45RBlow T cell-dependent mechanism.

Allergic asthma is currently considered a chronic airway inflammatory disorder associated with the presence of activated CD4(+) Th2-type lymphocytes, eosinophils, and mast cells. Interestingly, therapeutic strategies based on immune deviation and suppression have been shown to successfully attenuate the development of the asthma phenotype. In this investigation, we have for the first time used a genetically modified (GM) plant, narrow leaf lupin (Lupinus angustifolius L.), expressing a gene for a potential allergen (sunflower seed albumin) (SSA-lupin) to examine whether a GM plant/food-based vaccine strategy can be used to suppress the development of experimental asthma. We show that oral consumption of SSA-lupin promoted the induction of an Ag-specific IgG2a Ab response. Furthermore, we demonstrate that the plant-based vaccine attenuated the induction of delayed-type hypersensitivity responses and pathological features of experimental asthma (mucus hypersecretion, eosinophilic inflammation, and enhanced bronchial reactivity (airways hyperreactivity). The suppression of experimental asthma by SSA-lupin was associated with the production of CD4(+) T cell-derived IFN-gamma and IL-10. Furthermore, we show that the specific inhibition of experimental asthma was mediated via CD4(+)CD45RB(low) regulatory T cells and IFN-gamma. Thus, our data demonstrate that a GM plant-based vaccine can promote a protective immune response and attenuate experimental asthma, suggesting that plant-based vaccines may be potentially therapeutic for the protection against allergic diseases.

2S Albumins, Plant↗

PubMed2003

Antigen-specific production of interleukin (IL)-13 and IL-5 cooperate to mediate IL-4Ralpha-independent airway hyperreactivity.

The pathogenesis of human asthma and the development of key features of pulmonary allergy in mouse models has been critically linked to IL-13. Analyses of the receptor components employed by IL-13 have shown that delivery of this cytokine to the airways of naive IL-4Ralpha gene targeted (IL-4Ralpha(-/-)) mice fails to induce disease, suggesting that this membrane protein is critical for transducing IL-13-mediated responses. The current study demonstrates that, in contrast to naive mice, T helper 2 bias, airways hyperreactivity (AHR) and tissue eosinophilia develop in Ovalbumin-sensitized IL-4Ralpha(-/-) mice and that these responses can be inhibited by the IL-13 antagonist sIL-13Ralpha2Fc. Therefore, antigen stimulation induces an IL-13-regulated response that is independent of IL-4Ralpha. To determine the role of IL-5 and eosinophils in the development of disease in antigen-exposed IL-4Ralpha(-/-) mice, pulmonary allergy was examined in mice deficient in both factors. IL-4Ralpha/IL-5(-/-) mice were significantly defective in their ability to produce IL-13 and failed to develop AHR, suggesting that IL-5 indirectly regulates AHR in allergic IL-4Ralpha(-/-) mice by an IL-13-dependent mechanism. Collectively, these results demonstrate that IL-13-dependent processes regulating the development of AHR and T helper bias persist in the in the lungs of allergic IL-4Ralpha(-/-) mice.

Animals↗

PubMed2003

Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity.

BACKGROUND: Eotaxin-2 is a member of the eotaxin subfamily of CC chemokines that display eosinophil-specific, chemotactic properties and has been associated with allergic disorders. However, the contribution of eotaxin-2 to the development of defined pathogenic features of allergic disease remains to be defined. OBJECTIVE: We sought to determine whether eotaxin-2 was a cofactor with IL-5 for the regulation of pulmonary eosinophilia and to identify the combined role of these molecules in the induction of phenotypic characteristics of allergic lung disease. METHODS: We instilled recombinant eotaxin-2 into the airways of wild-type mice that had been treated systemically with IL-5 or into IL-5-transgenic mice and characterized pulmonary eosinophil numbers, IL-13 production, and airway hyperreactivity (AHR) to methacholine. Mice deficient in the IL-4 receptor alpha-chain, IL-13, and signal transducers and activators of transcription 6 or mice treated with anti-CCR3 monoclonal antibody were also used. RESULTS: Eotaxin-2 and IL-5 cooperatively promoted eosinophil accumulation, IL-13 production, and AHR to methacholine. Neither eotaxin-2 nor IL-5 alone induced these features of allergic disease. IL-13 production was critically dependent on eotaxin-2- and IL-5-regulated eosinophilia, which predisposed to the development of AHR. AHR was dependent on IL-13 and signaling through the IL-4R alpha-chain and signal transducers and activators of transcription 6 pathways and the presence of eosinophils in the lung. CONCLUSION: These investigations demonstrate important cooperativity between eotaxin-2, IL-5, and IL-13 signaling systems and eosinophils for the development of hallmark features of allergic disease of the lung.

Aerosols↗

PubMed2003

Chemokines in asthma: cooperative interaction between chemokines and IL-13.

The asthmatic response is characterized by elevated production of IgE, cytokines, chemokines, mucus hypersecretion, air-way obstruction, eosinophilia, and enhanced airway hyperreactivity to spasmogens. Clinical and experimental investigations have demonstrated a strong correlation between the presence of CD4+ TH2 cells, eosinophils, and disease severity, suggesting an integral role for these cells in the pathophysiology of asthma. TH2 cells are thought to induce asthma through the secretion of an array of cytokines (IL-4, -5, -9 -1),-13, -25) that activate inflammatory and residential effector pathways both directly and indirectly. In particular, IL-4 and IL-13 are produced at elevated levels in the asthmatic lung and are thought to be central regulators of many of the hallmark features of the disease. The potency of IL-13 in promoting airway hyperreactivity and mucus hypersecretion and the ability of IL-13 blockade to abrogate several critical aspects of experimental asthma have led to the view that this is a critical cytokine in disease pathogenesis. Extensive studies have also demonstrated a central role for chemokines in orchestrating multiple aspects of the asthmatic response. Chemokines are potent leukocyte chemoattractants, cellular activating factors, and histamine-releasing factors, which makes them particularly important in the pathogenesis of allergic inflammation. In particular, the eotaxin subfamily of chemokines and their receptor CC chemokine receptor 3 have emerged as central regulators of the asthmatic response. Recent studies have provided an integrated mechanism by which to explain the coordinate interaction between IL-13 and chemokines in the pathogenesis of asthma. In this regard, chemokines and IL-13 are attractive new therapeutic targets for the treatment of allergic disease. This article focuses on recently emerging data pertaining to the importance of chemokines, especially eotaxins, in promoting IL-13-associated allergic lung responses, as well as the potential for pharmacologically targeting these pathways.

Animals↗

PubMed2003

Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis.

BACKGROUND: Atopy has been linked to chromosome 11q22, a region that harbors the IL18 gene. IL-18 enhances IL-4/IL-13 production and induces IgE production that is directly associated with the pathogenesis of atopic disorders. OBJECTIVE: We sought to investigate whether genetic abnormalities in the regulatory regions of the IL18 gene predispose, in part, to susceptibility to atopy. METHODS: Among a white population of 105 families, the oldest child was examined with regard to atopic phenotypes and single-nucleotide polymorphisms (SNPs) within the IL18 gene. RESULTS: We have identified 5 novel SNPs in the IL18 gene (-920[t/c], -133[c/g], and -132[a/g] in promoter 2 [upstream of exon 2]; +179[c/a; Ser35Ser] in exon 4; and +486[c/t; Phe137Phe] in exon 6). Three SNPs are located in promoter 2, and one (-133[c/g]; nuclear factor 1 site) was significantly associated with high serum IgE levels (P =.001; odds ratio, 3.96) and specific sensitization to common allergens (P =.005; OR, 4.12). In addition, previously identified SNPs in exon 1 (+113[t/g] and +127[c/t]) and in promoter 1 (-137[g/c], GATA3 site) of the IL18 gene were significantly associated with high IgE levels (P < or =.005; OR, 3.27-3.90) and specific sensitization (P =.02 to.008; OR, 3.27-3.83). The SNP +127(g/t) in exon 1 was also a susceptibility locus for seasonal allergic rhinitis (P =.008; OR, 3.22). CONCLUSION: IL18 might be responsible for the linkage effects seen in the chromosomal region 11q22, which has been found previously with the phenotype "sensitization to mite allergen." Thus a suspected direct role of IL18 in the pathogenesis of atopy has been strengthened by the presence of 8 common SNPs in the promoter regions of IL18.

Alleles↗

PubMed2003

Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis.

Asthma is on the rise despite intense, ongoing research underscoring the need for new scientific inquiry. In an effort to provide unbiased insight into disease pathogenesis, we took an approach involving expression profiling of lung tissue from mice with experimental asthma. Employing asthma models induced by different allergens and protocols, we identified 6.5% of the tested genome whose expression was altered in an asthmatic lung. Notably, two phenotypically similar models of experimental asthma were shown to have distinct transcript profiles. Genes related to metabolism of basic amino acids, specifically the cationic amino acid transporter 2, arginase I, and arginase II, were particularly prominent among the asthma signature genes. In situ hybridization demonstrated marked staining of arginase I, predominantly in submucosal inflammatory lesions. Arginase activity was increased in allergen-challenged lungs, as demonstrated by increased enzyme activity, and increased levels of putrescine, a downstream product. Lung arginase activity and mRNA expression were strongly induced by IL-4 and IL-13, and were differentially dependent on signal transducer and activator of transcription 6. Analysis of patients with asthma supported the importance of this pathway in human disease. Based on the ability of arginase to regulate generation of NO, polyamines, and collagen, these results provide a basis for pharmacologically targeting arginine metabolism in allergic disorders.

Animals↗

PubMed2003

Regulation of eosinophil migration and Th2 cell function by IL-5 and eotaxin.

Asthma is characterized by elevated production of IgE, Th2 cytokines, chemokines, mucus hypersecretion, globlet cell metaplasia/hyperplasia, airway obstruction, eosinophilia and enhanced bronchial hyperresponsiveness. These hallmark features of asthma have all been linked to the effector functions of Th2 cytokines (e.g., interleukin-(IL)-4,5,9,10, and 13) in clinical and experimental investigations. This article will detail some of the pathogenic effects regulated by IL-13, IL-5 and the eotaxin subfamily of chemokines to regulate certain aspects of allergic disease. In particular, the potency of IL-13 in inducing enhanced bronchial responsiveness to spasmogenic stimuli and mucus hypersecretion suggests a key role of this molecule in the induction of airways obstruction. Recent studies also indicate that IL-5 and eotaxin, through eosinophils, may regulate Th2 cell function and IL-13 production from this lymphocyte. Therefore, IL-5 and IL-13 signaling systems are not necessarily mutually exclusive effector mechanisms, but may also be integrated through eosinophils to regulate certain aspects of allergic diseases. Blocking IL-13, or pathways that may promote IL-13-associated allergic lung responses (IL-5 and eotaxin) could provide an important strategy to improve the specificity of asthma therapy.

Animals↗

PubMed2002

Biochemical and functional characterization of human transmembrane tryptase (TMT)/tryptase gamma. TMT is an exocytosed mast cell protease that induces airway hyperresponsiveness in vivo via an interleukin-13/interleukin-4 receptor alpha/signal transducer and activator of transcription (STAT) 6-dependent pathway.

Transmembrane tryptase (TMT)/tryptase gamma is a membrane-bound serine protease stored in the secretory granules of human and mouse lung mast cells (MCs). We now show that TMT reaches the external face of the plasma membrane when MCs are induced to degranulate. Analysis of purified recombinant TMT revealed that it is a two-chain neutral protease. Thus, TMT is the only MC protease identified so far which retains its 18-residue propeptide when proteolytically activated. The genes that encode TMT and tryptase betaI reside on human chromosome 16p13.3. However, substrate specificity studies revealed that TMT and tryptase betaI are functionally distinct even though they are approximately 50% identical. Although TMT is rapidly inactivated by the human plasma serpin alpha(1)-antitrypsin in vitro, administration of recombinant TMT (but not recombinant tryptase betaI) into the trachea of mice leads to airway hyperresponsiveness (AHR) and increased expression of interleukin (IL) 13. T cells also increase their expression of IL-13 mRNA when exposed to TMT in vitro. TMT is therefore a novel exocytosed surface mediator that can stimulate those cell types that are in close proximity. TMT induces AHR in normal mice but not in transgenic mice that lack signal transducer and activator of transcription (STAT) 6 or the alpha-chain of the cytokine receptor that recognizes both IL-4 and IL-13. Based on these data, we conclude that TMT is an exocytosed MC neutral protease that induces AHR in lungs primarily by activating an IL-13/IL-4Ralpha/STAT6-dependent pathway.

Animals↗

PubMed2002

Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma.

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti-IL-5 or anti-IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin(-/-)) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4(+) T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin(-/-) mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.

Adoptive Transfer↗