Chest
Volume 151, Issue 6, June 2017, Pages 1338-1344
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Translating Basic Research Into Clinical Practice
Epithelial-Derived Cytokines in Asthma

https://doi.org/10.1016/j.chest.2016.10.042Get rights and content

The interaction between the airway epithelium and the inhaled environment is crucial to understanding the pathobiology of asthma. Several studies have identified an important role of airway epithelial-derived cytokines, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) in asthma pathogenesis. These cytokines have been described as epithelial-derived alarmins that activate and potentiate the innate and humoral arms of the immune system in the presence of actual or perceived damage. Each of the three epithelial-derived alarmins has been implicated in the pathobiology of inhaled allergen-induced airway responses. The best evidence to date exists for TSLP, in that a human monoclonal antibody, which binds TSLP and prevents its engagement with its receptor, resolves airway inflammation in patients with allergic asthma and attenuates allergen-induced airway responses. Better understanding the roles that the epithelial-derived alarmins play and how they influence airway immune response may allow the development of novel therapeutics for asthma treatment.

Section snippets

Epithelial-Derived IL-25

IL-25 is an epithelial-derived cytokine that is also known as IL-17E. It is a member of the IL-17 cytokine family and is expressed by airway epithelial cells, T-helper-2 polarized cells, activated mast cells, basophils, and eosinophils.7, 8 IL-25 is unique among the IL-17 family of cytokines, in that it can initiate eosinophilia and upregulate type 2 cytokine production.9 IL-25 is stored in, and released from, the extranuclear cellular compartment. It is constitutively expressed in epithelial

Epithelial-Derived IL-33

IL-33 is a member of the IL-1 cytokine family.20 Epithelial cells from tissues exposed to the external environment, such as eyes, skin, intestine, and airways, and lymphoid organs, keratinocytes, smooth muscle cells, and human endothelial cells produce IL-33.21, 22 Immune cells also express IL-33, including macrophages, DCs, mast cells, and monocytes, but at a 10-fold lower level than epithelial cells.23, 24 IL-33 is not expressed in CD45+ve hematopoietic cells under basal conditions, but it

Epithelial-Derived TSLP

TSLP is part of the IL-2 cytokine family, the gene for which is localized on chromosome 5q22.1, which is next to the atopic cytokine gene cluster, 5q31, which encodes IL-4, IL-5, IL-9, and IL-13. TSLP binds to a high-affinity receptor complex that consists of the thymic stromal lymphopoietin receptor (TSLPR) and an IL-7Rα subunit. The receptor is expressed on many cell types, which include myeloid DCs, CD4+ve and CD8+ve T cells, regulatory T cells, B cells, mast cells, NKT cells, monocytes,

Conclusions

There has been great progress in the study of the responses of the airway epithelium to allergens and infection. The airway epithelium constitutes the first physical, chemical, and immunologic barrier to inhaled agents. Epithelial cells express pattern recognition receptors, integrate information from many receptors simultaneously, and bridge the innate and adaptive immune system cells through the release of chemokines and cytokines.

Evidence is accumulating that epithelial-derived alarmins,

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: P. O. B. reports grants and personal fees from AstraZeneca, personal fees from Chiesi, grants from Novartis, personal fees from Boehringer Ingelheim, personal fees from GSK, personal fees from MedImmune, personal fees from Merck, personal fees from Abbott, grants from Amgen, grants from Genentech, and grants from Axican outside the submitted work. None declared (P. D. M.).

Other contributions: We thank Mark

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