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A7179 - Inter-Individual Differences in Airway Epithelial Cell Responses to IL-13, a Key Cytokine in Type 2-High Asthma
Author Block: K. Koh1, L. R. Bonser1, W. L. Eckalbar1, J. L. Pollack1, L. T. Zlock2, N. R. Bhakta1, W. E. Finkbeiner2, P. G. Woodruff1, D. J. Erle1; 1Medicine, University of California, San Francisco, San Francisco, CA, United States, 2Pathology, University of California, San Francisco, San Francisco, CA, United States.
Rationale: Mucus hypersecretion and airway obstruction are prominent features of asthma. IL-13 directly acts on airway epithelial cells to induce MUC5AC, and high levels of MUC5AC cause mucostasis and airway obstruction in type 2-high asthma. Recent findings suggest that inter-individual differences in airway epithelial cell responsiveness to IL-13 could be major determinants of asthma susceptibility and severity.
Hypothesis: The ability of IL-13 to induce expression of MUC5AC differs widely between individuals.
Methods: Human bronchial epithelial (HBE) cells from 10 donors were cultured at air-liquid interface (ALI) in the absence or in the presence of IL-13. RNA-seq (experiment 1, 6 donors) or qRT-PCR (experiment 2, 8 donors) was performed to measure the levels of MUC5AC and other IL-13–inducible genes. In addition, we analyzed our published RNA-seq data from bronchial brushings of individuals with asthma to examine correlations between these IL-13-inducible genes.
Results: IL-13 induced MUC5AC and many other known IL-13–inducible genes in cultured HBE cells from all 10 subjects. The extent of induction was similar across donors for most IL-13-inducible genes. However, the degree of MUC5AC induction varied considerably between donors (>30-fold range) without any significant correlation to expression of other IL-13–inducible genes, including those that encode transcription factors with key roles in differentiation of MUC5AC-producing goblet cells (SPDEF, FOXA3) and other proteins secreted by these cells (SERPINB2, FCGBP, ITLN1). Analysis of expression levels in bronchial brushings from individuals with type 2-high asthma showed that levels of many IL-13-inducible genes were highly correlated with levels of three previously identified type 2 signature genes, POSTN, CLCA1, and SERPINB2. Although MUC5AC was increased in individuals with type 2-high asthma, levels of MUC5AC were not well correlated with levels of the three type 2 signature genes or the goblet cell-specific transcription factors SPDEF and FOXA3.
Conclusions: There are large inter-individual differences in the extent of MUC5AC induction in response to IL-13. These differences do not reflect general differences in IL-13 responsiveness since induction of other goblet cell genes does not exhibit similar inter-individual variation. Our results suggest that IL-13 activity is the major determinant of goblet cell differentiation and expression of many goblet cell genes, whereas expression of MUC5AC is determined both by IL-13 activity and by unknown factors that differ between individuals. Further work is underway to investigate the basis of this altered sensitivity and determine its relationship to type 2-high asthma susceptibility and severity.