Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma.

Alexander, A. G.; Barkans, J.; Moqbel, Redwan; Barnes, Neil; Kay, A. B.; Corrigan, Chris J.

doi:10.1136/thx.49.12.1231

Cited by 47 publications

(29 citation statements)

References 6 publications

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“…To learn whether IL-5 stimulates static adhesion to the soluble VCAM-1 splice forms, EOS were incubated with IL-5 and studied in cell adhesion assays. EOS incubated with 50 pg/ml IL-5, a concentration within the physiological range measured in the serum of human asthmatics (42)(43)(44), exhibited an ϳ1.5-fold enhancement in maximum adhesion to both 6d-VCAM-1 ( Fig. 2A) and 7d-VCAM-1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Such EOS recruited to the asthmatic airway exhibit increased ␣M␤2 expression compared with EOS in blood (78 -80). Activation of ␣M␤2 (45,77) and formation of podosomes of EOS (25), structures believed important in cell migration (70), are induced by exposure to IL-5, which is up-regulated in the blood and airway of human asthmatics (42,(81)(82)(83). In addition, the chemokines RANTES (regulated on activation, normal T-cell expressed and secreted), monocyte chemotactic protein-3, and complement activation factor-5 expose an activation-sensitive epitope of ␣M␤2 (84) and promote migration of blood EOS (84 -87).…”

Section: Discussionmentioning

confidence: 99%

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Differential Engagement of Modules 1 and 4 of Vascular Cell Adhesion Molecule-1 (CD106) by Integrins α4β1 (CD49d/29) and αMβ2 (CD11b/18) of Eosinophils

Barthel

Annis

Mosher

et al. 2006

Journal of Biological Chemistry

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We have studied adhesion of eosinophils to various forms of vascular cell adhesion molecule 1 (VCAM-1, CD106), an integrin counter-receptor implicated in eosinophil recruitment to the airway in asthma. Full-length 7d-VCAM-1, with seven immunoglobulin-like modules, contains integrin-binding sites in modules 1 and 4. The alternatively spliced six-module protein, 6d-VCAM-1, lacks module 4. In static assays, unactivated purified human blood eosinophils adhered similarly to recombinant soluble human 6d-VCAM-1 and 7d-VCAM-1 coated onto polystyrene microtiter wells. Further experiments, however, revealed differences in recognition of modules 1 and 4. Antibody blocking indicated that eosinophil adhesion to 6d-VCAM-1 or a VCAM-1 construct containing only modules 1-3, 1-3VCAM-1, is mediated by ␣4␤1 (CD49d/29) ,whereas adhesion to a construct containing modules 4 -7, 4 -7VCAM-1, is mediated by both ␣4␤1 and ␣M␤2 (CD11b/18). Inhibitors of phosphoinositide 3-kinase, which block adhesion of eosinophils mediated by ␣M␤2, blocked adhesion to 4 -7VCAM-1 but had no effect on adhesion to 6d-VCAM-1. Consistent with the antibody and pharmacological blocking experiments, eosinophilic leukemic cell lines lacking ␣M␤2 did not adhere to 4 -7VCAM-1 but did adhere to 6d-VCAM-1 or 1-3VCAM-1. Activation of eosinophils by interleukin (IL)-5 enhanced static adhesion to 6d-VCAM-1, 7d-VCAM-1, or 4 -7VCAM-1; IL-5-enhanced adhesion to all 3 constructs was blocked by anti-␣M␤2. Adhesion of unstimulated eosinophils to 7d-VCAM-1 under flow conditions was inhibited by anti-␣4 or anti-␣M. IL-5 treatment decreased eosinophil adhesion to 7d-VCAM-1 under flow, and anti-␣M had the paradoxical effect of increasing adhesion. These results demonstrate that ␣M␤2 modulates ␣4␤1-mediated eosinophil adhesion to VCAM-1 under both static and flow conditions. Vascular cell adhesion molecule 1 (VCAM-1)2 is a multimodular cell-surface glycoprotein up-regulated on human endothelium in response to pro-inflammatory cytokines in the asthmatic lung (1) and has been implicated in recruitment of eosinophils (EOS) from blood to the airway in asthma (2). Heterodimeric integrin receptors interacting with VCAM-1 are important in the rolling, firm adhesion, and movement of EOS (3, 4). These events are regulated by cytokines, which may alter integrin adhesive activity (5, 6). EOS express at least three potential integrin receptors that may be involved in adhesion to VCAM-1: ␣4␤1 (7-9), ␣D␤2 (7), and ␣4␤7 (8 -11).Considerable information is available about features of human VCAM-1 that are important for adhesion. The loop between ␤ strands C and D in the first immunoglobulin (Ig)-like module is accessible on the protein surface and contains the core integrin-recognition sequence Ile 39 -Asp-Ser-Pro-Leu 43 (IDSPL) (11-15). A second IDSPL site is present in the CD loop in module 4 (12, 14). Based on topology of exons within the mammalian genome and the similarity in amino acid sequence, a three-module unit was likely duplicated to generate VCAM-1 modules 1-3 and 4 -6 (16, 17). Modul...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential Engagement of Modules 1 and 4 of Vascular Cell Adhesion Molecule-1 (CD106) by Integrins α4β1 (CD49d/29) and αMβ2 (CD11b/18) of Eosinophils

Barthel

Annis

Mosher

et al. 2006

Journal of Biological Chemistry

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“…In asthma, IL-5 levels are often elevated in the lung and blood, suggesting that this cytokine has the potential to regulate eosinophil function in both compartments (29). Although IL-5 and eotaxin cooperate to selectively regulate tissue eosinophilia, the role of these cytokines in regulating blood and airways eosinophilia, eosinophil degranulation, and AHR when expressed in the lung has not been fully determined.…”

mentioning

confidence: 99%

“…Eotaxin may also regulate the mobilization of eosinophils and their precursors into the blood (23,25,26). IL-5 regulates the growth, differentiation, and activation of eosinophils, and has been strongly implicated in the etiology of asthma (27)(28)(29)(30)(31)(32). Studies with IL-5-deficient (IL-5 Ϫ/Ϫ ) mice indicate that this cytokine provides an essential signal for the induction of blood and pronounced tissue eosinophilia that is observed during allergic lung inflammation (33).…”

mentioning

confidence: 99%

The Effect of IL-5 and Eotaxin Expression in the Lung on Eosinophil Trafficking and Degranulation and the Induction of Bronchial Hyperreactivity

Mould

Ramsay

Matthaei³

et al. 2000

The Journal of Immunology

172

119

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The mechanisms regulating the selective migration and degranulation of eosinophils in the asthmatic lung and the subsequent development of airways hyperreactivity (AHR) have not been fully delineated. In this investigation, we have employed a novel transgene model to facilitate the dissection of the contributions of IL-5 and/or eotaxin to eosinophil function in the absence of complex tissue signals derived from the allergic lung. Gene transfer of IL-5 and/or eotaxin to the lungs of naive mice induced a pronounced and selective airways eosinophilia, but did not result in eosinophil degranulation or AHR. Airways eosinophilia occurred independently of the induction of a blood eosinophilia, but was markedly augmented by the coexpression of both cytokines and/or by the transient mobilization of eosinophils from the bone marrow by the administration of i.v. IL-5. However, for eosinophil degranulation and AHR to occur, the inhalation of Ag was required in association with IL-5 and eotaxin expression. Investigations in IL-5-deficient mice linked eosinophilia, and not solely IL-5 and eotaxin, with the induction of AHR. Furthermore, eosinophil degranulation and AHR were dependent on CD4+ T cells. Importantly, this investigation shows that IL-5 regulates eosinophilia within the lung as well as in the circulation and also amplifies eotaxin-induced chemotaxis in the airway compartment. Moreover, the interplay between these cytokines, CD4+ T cells, and factors generated by Ag inhalation provides fundamental signals for eosinophil degranulation and the induction of AHR.

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“…Studies that have examined IL-5 expression in BAL and peripheral blood of asthmatic subjects before and after steroids have shown that the number of IL-5 mRNA positive cells is significantly decreased following oral corticosteroid treatment in steroid-sensitive asthma . In contrast, steroid resistant asthma and chronic severe steroid dependent asthma are associated with persistently elevated IL-5 mRNA levels (Leung et al 1995) and serum IL-5 levels (Alexander et al 1994), respectively . The decreases in the expression of IL-5 that followed corticosteroid therapy have been associated with decreased eosinophil numbers -especially in the peripheral blood , but increased numbers of IFN-γ positive cells in the bronchial mucosa and BAL fluid of asthmatic subjects , Leung et al 1995, Bentley et al 1996.…”

Section: Asthma and Il-5 Human Studies: Il5 Mrna And Proteinmentioning

confidence: 99%

IL-5 and IL-5 receptor in asthma

Kotsimbos

Hamid

1997

Mem. Inst. Oswaldo Cruz

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and a soluble isoform (αIL-5Rs). Cytokines such as IL-5 produce specific and non-specific cellular responses through specific cell membrane receptor mediated activation of intracellular signal transduction pathways which, to a large part, regulate gene expression. The major intracellular signal transduction mechanism is activation of non-receptor associated tyrosine kinases including JAK and MAP kinases which can then transduce signals via a novel family of transcriptional factors named signal transducers and activators of transcription (STATS). JAK2, STAT1 and STAT 5 appear to be particularly important in IL-5 mediated eosinophil responses. Asthma is characterized by episodic airways obstruction, increased bronchial responsiveness, and airway inflammation. Several studies have shown an association between the number of activated T cells and eosinophils in the airways and abnormalities in FEV1, airway reactivity and clinical severity in asthma. It has now been well documented that IL-5 is highly expressed in the bronchial mucosa of atopic and intrinsic asthmatics and that the increased IL-5 mRNA present in airway tissues is predominantly T cell derived. Immunocytochemical staining of bronchial biopsy sections has confirmed that IL-5 mRNA transcripts are translated into protein in asthmatic subjects. Furthermore, the number of activated CD 4 + T cells and IL-5 mRNA positive cells are increased in asthmatic airways following antigen challenge and studies that have examined IL-5 expression in asthmatic subjects before and after steroids have shown significantly decreased expression following oral corticosteroid treatment in steroid-sensitive asthma but not in steroid resistant and chronic severe steroid dependent asthma. The link between T cell derived IL-5 and eosinophil activation in asthmatic airways is further strengthened by the demonstration that there is an increased number of αIL-5R mRNA positive cells in the bronchial biopsies of atopic and non-atopic asthmatic subjects and that the eosinophil is the predominant site of this increased

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Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma.

Cited by 47 publications

References 6 publications

Differential Engagement of Modules 1 and 4 of Vascular Cell Adhesion Molecule-1 (CD106) by Integrins α4β1 (CD49d/29) and αMβ2 (CD11b/18) of Eosinophils

Differential Engagement of Modules 1 and 4 of Vascular Cell Adhesion Molecule-1 (CD106) by Integrins α4β1 (CD49d/29) and αMβ2 (CD11b/18) of Eosinophils

The Effect of IL-5 and Eotaxin Expression in the Lung on Eosinophil Trafficking and Degranulation and the Induction of Bronchial Hyperreactivity

IL-5 and IL-5 receptor in asthma

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