Effect of Inhaled Interleukin-5 on Airway Hyperreactivity and Eosinophilia in Asthmatics

Shi, Huan‐Zhong; Xiao, Changqing; Zhong, Ding; Qin, Simeng; Liu, Yi; Gao, Liang; Xu, Hui; Chen, Yiqiang; Long, Xue-Ming; Xie, Zijian

doi:10.1164/ajrccm.157.1.9703027

Cited by 163 publications

(84 citation statements)

References 33 publications

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“…More importantly, the ability of IL-5 administration after the onset of sepsis to significantly improve survival in mice suggests that IL-5 is an effective rescue therapy. Interestingly, IL-5 has been administered safely to patients with asthma as part of studies investigating leukocyte recruitment, further emphasizing its viability as a therapeutic adjuvant (43). Although numerous studies demonstrate a role for IL-5 in modulation of Th2 polarization in allergic diseases and a protective role in response to various parasitic infections, to our knowledge this is the first time it has been investigated in any acute bacterial or infectious disorder.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

Linch

Danielson

Kelly

et al. 2012

Am J Respir Crit Care Med

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Rationale: The immune response in sepsis is characterized by overt immune dysfunction. Studies indicate immunostimulation represents a viable therapy for patients. One study suggests a potentially protective role for interleukin 5 (IL-5) in sepsis; however, the loss of eosinophils in this disease presents a paradox. Objectives: To assess the protective and eosinophil-independent effects of IL-5 in sepsis. Methods: We assessed the effects of IL-5 administration on survival, bacterial burden, and cytokine production after polymicrobial sepsis. In addition, we examined the effects on macrophage phagocytosis and survival using fluorescence microscopy and flow cytometry. Measurements and Main Results: Loss of IL-5 increased mortality and tissue damage in the lung, IL-6 and IL-10 production, and bacterial burden during sepsis. Therapeutic administration of IL-5 improved mortality in sepsis. Interestingly, IL-5 administration resulted in neutrophil recruitment in vivo. IL-5 overexpression in the absence of eosinophils resulted in decreased mortality from sepsis and increased circulating neutrophils and monocytes, suggesting their importance in the protective effects of IL-5. Furthermore, novel data demonstrate IL-5 receptor expression on neutrophils and monocytes in sepsis. IL-5 augmented cytokine secretion, activation, phagocytosis, and survival of macrophages. Importantly, macrophage depletion before the onset of sepsis eliminated IL-5-mediated protection. The protective effects of IL-5 were confirmed in humans, where IL-5 levels were elevated in patients with sepsis. Moreover, neutrophils and monocytes from patients expressed the IL-5 receptor. Conclusions: Taken together, these data support a novel role for IL-5 on noneosinophilic myeloid populations, and suggest treatment with IL-5 may be a viable therapy for sepsis.

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Section: Discussionmentioning

confidence: 99%

Interleukin 5 Is Protective during Sepsis in an Eosinophil-Independent Manner

Linch

Danielson

Kelly

et al. 2012

Am J Respir Crit Care Med

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“…Administration of recombinant IL-5 into the airways of either guinea pigs (8) or mildly asthmatic individuals (9) promotes a lung eosinophilia and bronchial hyperreactivity. Moreover, blocking the activity of IL-5 through administration of neutralizing anti-IL-5 antibodies (10-12), or through IL-5 gene deletion (13), prevents allergen-induced airway eosinophilia and bronchial hyperreactivity.…”

mentioning

confidence: 99%

A potent dimeric peptide antagonist of interleukin-5 that binds two interleukin-5 receptor α chains

England

Palaniappan

Uings

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Two series of peptides that specifically bind to the extracellular domain of the ␣ chain of the human interleukin-5 receptor (IL-5R␣), but share no primary sequence homology to IL-5, were identified from libraries of random recombinant peptides. Affinity maturation procedures generated a 19-aa peptide that binds to the IL-5 receptor ␣͞␤ heterodimer complex with an affinity equal to that of IL-5 and is a potent and specific antagonist of IL-5 activity in a human eosinophil adhesion assay. The active form of the peptide is a disulfide-crosslinked dimer that forms spontaneously in solution. Gel filtration analysis, receptor-binding studies, and analytical ultracentrifugation reveal that the dimeric peptide binds simultaneously to two receptor ␣ chains in solution. Furthermore, the dimer peptide, but not IL-5, can activate a chimeric receptor consisting of the IL-5R␣ extracellular domain fused to the intracellular domain of the epidermal growth factor receptor, thus demonstrating that the peptide also promotes receptor dimerization in a cellular context. The functional antagonism produced by the bivalent interaction of the dimeric peptide with two IL-5R ␣ chains represents a distinctive mechanism for the antagonism of cytokines that use heteromeric receptors.I nterleukin-5 (IL-5) is a T cell-derived hematopoietic cytokine that acts exclusively on cells of the eosinophil and basophil lineage (1, 2). Although IL-5 can regulate many of the functions of mature, terminally differentiated eosinophils such as cell survival (3), adhesion (4), and activation (5), its primary function is to promote the differentiation and expansion of eosinophil precursors in the bone marrow (6).Transgenic mice that constitutively overexpress IL-5 in their lungs exhibit systemic and airway eosinophilia, bronchial hyperreactivity, and histopathological features characteristic of human asthma (7). Administration of recombinant IL-5 into the airways of either guinea pigs (8) or mildly asthmatic individuals (9) promotes a lung eosinophilia and bronchial hyperreactivity. Moreover, blocking the activity of IL-5 through administration of neutralizing anti-IL-5 antibodies (10-12), or through IL-5 gene deletion (13), prevents allergen-induced airway eosinophilia and bronchial hyperreactivity. Together, these data demonstrate that IL-5 plays a central role in the development of allergen-induced eosinophilia in animals and suggest that an anti-IL-5 therapeutic could provide an alternative approach to the treatment of human asthma perhaps more specific than current anti-inf lammatory therapies such as inhaled corticosteroids.The IL-5 receptor is a heterodimer consisting of an ␣ chain that specifically binds IL-5 and a signal-transducing ␤ c chain shared with the receptors for two structurally related cytokines: granulocyte-macrophage colony-stimulating factor (GM-CSF) and . A number of protein-based IL-5 antagonists have been reported, including soluble IL-5 receptor ␣ chains (IL5R␣s) that sequester the ligand in solution (15), single point mutants of IL...

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“…Interventions altering airway inflammation are effective in changing the degree of airway responsiveness. For example, AHR can be increased in asthmatics following the induction of acute inflammation by inhalation of allergens (47,143) or IL-5 (218). On the other hand, reducing inflammation by the use of glucocorticoids attenuates AHR (reviewed in (30)).…”

Section: Airway Inflammationmentioning

confidence: 99%

“…These results may offer an explanation for the failure of ex vivo studies to show an increased strength of ASM from asthmatics (reviewed in (153)). The ability of ASM to rapidly change its contractile capacity in response to inflammatory molecules can also contribute to changes in airway responsiveness observed in response to interventions altering airway inflammation (30,47,143,218). Those are all different ways by which a normal ASM may account for AHR in an inflamed environment.…”

Section: Inflammatory Cells and Moleculesmentioning

confidence: 99%