Epithelial cytokine production and differentiation are two processes known to be dysregulated in mucosal inflammatory disorders. We have discovered that the nuclear cytokine IL-33 is selectively present in the epithelium within the nuclei of basal layer epithelial cells in patients with eosinophilic esophagitis (EoE), an emerging allergic inflammatory disease of the esophagus. EoE is an unmet medical need as it is relatively poorly understood, growing in incidence, and currently has no FDA-approved treatment. IL-33 is well-known to promote allergic inflammation through extracellular release and activation of immune cells through the ST2 receptor. However, IL-33 can also regulate gene transcription in the absence of extracellular release. In line with this, upon overexpression of IL-33 in an ST2-deficient esophageal epithelial cell line, we noted altered expression of inflammatory cytokines and the epithelial differentiation marker keratin 10. The objective of the present work is to elucidate the involvement of nuclear IL-33 in the pathogenesis of allergic inflammation, particularly related to EoE. We hypothesize that nuclear IL-33 regulates epithelial cell differentiation, proliferation, and cytokine expression through modulating chromatin structure.
Aim one of this proposal will assess the ability of IL-33 to directly bind chromatin and modulate its structure in esophageal epithelial cells.
Aim two will assess the mechanism by which IL-33 regulates gene transcription.
Aim three will assess the effect of intracellular IL-33 on epithelial cell proliferation and differentiation. This work has the potential to uncover basic biology of IL-3 and the opportunity to create a novel paradigm for the role of IL-33 in allergic inflammation, possibly providing better strategies for therapeutic intervention in EoE and other allergic diseases.

Public Health Relevance

Approximately 1 in 2000 children is affected with the emerging allergic disorder eosinophilic esophagitis (EoE). The pro-allergic cytokine IL-33 is increased in the nuclei of epithelial cells in patients with active EoE. This proposal aims to determine the role of nuclear expression of IL-33 in its pathogenesis. The regulation of gene transcription by IL-33 in the absence of extracellular release could present a new paradigm for the role of IL-33 in allergic inflammation and facilitate development of novel approaches to treatment

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1)
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Densmore, Christine L
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University of Cincinnati
Schools of Medicine
United States
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Travers, Jared; Rochman, Mark; Miracle, Cora E et al. (2018) Chromatin regulates IL-33 release and extracellular cytokine activity. Nat Commun 9:3244
Rochman, Mark; Travers, Jared; Miracle, Cora E et al. (2017) Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis. J Allergy Clin Immunol 140:738-749.e3
Travers, J; Rochman, M; Caldwell, J M et al. (2017) IL-33 is induced in undifferentiated, non-dividing esophageal epithelial cells in eosinophilic esophagitis. Sci Rep 7:17563
Rochman, Mark; Travers, Jared; Abonia, J Pablo et al. (2017) Synaptopodin is upregulated by IL-13 in eosinophilic esophagitis and regulates esophageal epithelial cell motility and barrier integrity. JCI Insight 2: