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Molecular Mechanisms of Synergy Between IL-13 and IL-17A in Severe Asthma

Hall, Sara L, M.S.
http://orcid.org/0000-0002-1294-8208
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505125099399164

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Immunology.
Increased IL-17A production has been associated with more severe asthma; however, the mechanisms whereby IL-17A can contribute to IL-13-driven pathology in asthmatic patients remain unclear. In this thesis, we sought to elucidate the molecular mechanisms by which IL-17A enhances IL-13-dependent airway pathology in patients with severe asthma using in vivo and in vitro systems. We have found that compared to mice given intratracheal (i.t.) IL-13 alone, those co-exposed to IL-13 + IL-17A demonstrate enhanced airway hyperresponsiveness (AHR), mucus production, airway inflammation, and IL-13-induced gene expression. In vitro, IL-17A directly enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating effect of IL-17A on IL-13-driven responses, co-treatment with IL-13 diminished IL-17A-driven gene expression in vivo and in vitro. Mechanistically, in vivo and in primary human and murine cells, the IL-17A mediated increase in IL-13-induced gene expression was associated with a rapid increase in IL-13-driven signal transducer and activator of transcription (STAT)6 phosphorylation. Disrupting protein-tyrosine phosphatase function using Na3VO4 abrogated IL-17A-mediated enhancement of IL-13-driven STAT6 phosphorylation, suggesting that the ability of IL-17A to augment IL-13 activity was driven by changes in protein-tyrosine phosphatase activity. Consistent with this, co-exposure to IL-13 + IL-17A triggered a rapid decrease in the phosphorylation of Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2, negative regulators of IL-13 signal transduction. Pharmacologic inhibition of SHP-1 but not SHP-2 similarly abrogated IL-17A-mediated enhancement of IL-13-driven STAT6 phosphorylation. However, the ability of IL-17A-driven alterations in protein-tyrosine phosphatase activity to enhance cytokine signaling was specific for IL-13, as IL-17A had no effect on IL-6- and IFN-γ-dependent activation of STAT3 and STAT1, respectively. Surprisingly, the enhancement of STAT6 phosphorylation was not sufficient to explain IL-17A-mediated increases in IL-13-driven gene expression. Although IL-13 and IL-17A activate distinct cellular signaling pathways, we have identified specific transcription factors downstream of the IL-17A/Act1/TRAF6 signaling axis that influence transcriptional enhancement between IL-13 and IL-17A. Inhibition of NF-κB or C/EBPß and C/EBPd transcription factors partially attenuated IL-17A-mediated enhancement of IL-13-induced gene expression, while the inhibition of p38 mitogen-activated protein kinase (MAPK) completely abrogated the effect of IL-17A in cells co-exposed to IL-13 + IL-17A. However, the inhibition of p38 MAPK did not diminish IL-17A-mediated enhancement of STAT6 phosphorylation, implying that IL-17A signaling differentially regulates the accumulation of IL-13-induced STAT6 activation and gene expression. Collectively, our data suggest that IL-17A contributes to asthma pathophysiology by: 1)
Ian Paul Lewkowich, Ph.D. (Committee Chair)
Senad Divanovic, Ph.D. (Committee Member)
Fred Finkelman, M.D. (Committee Member)
Timothy Lecras, Ph.D. (Committee Member)
Matthew Weirauch, Ph.D. (Committee Member)
167 p.
Surgery
Asthma; IL-13; IL-17A; STAT6; Cytokine; Signal transduction

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Citations

  • Hall, S. L. (2017). Molecular Mechanisms of Synergy Between IL-13 and IL-17A in Severe Asthma [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505125099399164

    APA Style (7th edition)

  • Hall, Sara. Molecular Mechanisms of Synergy Between IL-13 and IL-17A in Severe Asthma. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505125099399164.

    MLA Style (8th edition)

  • Hall, Sara. "Molecular Mechanisms of Synergy Between IL-13 and IL-17A in Severe Asthma." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505125099399164

    Chicago Manual of Style (17th edition)

ucin1505125099399164
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This open access ETD is published by University of Cincinnati and OhioLINK.