The IL-4/IL-13 signaling axis promotes prostatic fibrosis
dc.contributor.author | D’Arcy, Q | |
dc.contributor.author | Gharaee-Kermani, M | |
dc.contributor.author | Zhilin-Roth, A | |
dc.contributor.author | Macoska, JA | |
dc.contributor.editor | Zissel, Gernot | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-02-03T15:30:14Z | |
dc.date.available | 2024-02-03T15:30:14Z | |
dc.date.issued | 2022-10-01 | |
dc.identifier.issn | 1932-6203 | |
dc.identifier.issn | 1932-6203 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/36201508 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/192259 | en |
dc.description.abstract | Background Lower urinary tract symptoms (LUTS) are a costly and pervasive medical problem for millions of aging men. Recent studies have showed that peri-urethral tissue fibrosis is an untreated pathobiology contributing to LUTS. Fibrosis results from excessive extracellular matrix deposition which increases transition zone and peri-urethral tissue stiffness and compromises prostatic urethral flexibility and compliance, producing urinary obstructive symptoms. Inflammatory cells, including neutrophils, macrophages, and T-lymphocytes, secrete a medley of pro-fibrotic proteins into the prostatic microenvironment, including IFNγ, TNFα, CXC-type chemokines, and interleukins, all of which have been implicated in inflammation-mediated fibrosis. Among these, IL-4 and IL-13 are of particular interest because they share a common signaling axis that, as shown here for the first time, promotes the expression and maintenance of IL-4, IL-13, their cognate receptors, and ECM components by prostate fibroblasts, even in the absence of immune cells. Based on studies presented here, we hypothesize that the IL-4/IL-13 axis promotes prostate fibroblast activation to ECM-secreting cells. Methods N1 or SFT1 immortalized prostate stromal fibroblasts were cultured and treated, short- or long-term, with pro-fibrotic proteins including IL-4, IL-13, TGF-β, TNF-α, IFNγ, with or without prior pre-treatment with antagonists or inhibitors. Protein expression was assessed by immunohistochemistry, immunofluorescence, ELISA, immunoblot, or Sircoll assays. Transcript expression levels were determined by qRT-PCR. Intact cells were counted using WST assays. Results IL-4Rα, IL-13Rα1, and collagen are concurrently up-regulated in human peri-urethral prostate tissues from men with LUTS. IL-4 and IL-13 induce their own expression as well as that of their cognate receptors, IL-4Rα and IL-13Rα1. Low concentrations of IL-4 or IL-13 act as cytokines to promote prostate fibroblast proliferation, but higher (>40ng/ml) concentrations repress cellular proliferation. Both IL-4 and IL-13 robustly and specifically promote collagen transcript and protein expression by prostate stromal fibroblasts in a JAK/STAT-dependent manner. Moreover, IL-4 and IL-13-mediated JAK/STAT signaling is coupled to activation of the IL-4Rα receptor. Conclusions Taken together, these studies show that IL-4 and IL-13 signal through the IL-4Rα receptor to activate JAK/STAT signaling, thereby promoting their own expression, that of their cognate receptors, and collagens. These finding suggest that the IL-4/IL-13 signaling axis is a powerful, but therapeutically targetable, pro-fibrotic mechanism in the lower urinary tract. | |
dc.format.medium | Electronic-eCollection | |
dc.language | eng | |
dc.publisher | Public Library of Science (PLoS) | |
dc.relation.haspart | ARTN e0275064 | |
dc.rights | Licence for published version: Creative Commons Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Chemokines, CXC | |
dc.subject | Collagen | |
dc.subject | Fibrosis | |
dc.subject | Humans | |
dc.subject | Interleukin-13 | |
dc.subject | Interleukin-13 Receptor alpha1 Subunit | |
dc.subject | Interleukin-4 | |
dc.subject | Interleukins | |
dc.subject | Lower Urinary Tract Symptoms | |
dc.subject | Male | |
dc.subject | Prostate | |
dc.subject | Transforming Growth Factor beta | |
dc.subject | Tumor Necrosis Factor-alpha | |
dc.title | The IL-4/IL-13 signaling axis promotes prostatic fibrosis | |
dc.type | Article | |
dc.identifier.pmid | 36201508 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/192259/2/The IL-4IL-13 signaling axis promotes prostatic fibrosis.pdf | |
dc.identifier.doi | 10.1371/journal.pone.0275064 | |
dc.identifier.doi | https://dx.doi.org/10.7302/22168 | |
dc.identifier.source | PLoS ONE | |
dc.description.version | Published version | |
dc.date.updated | 2024-02-03T15:30:09Z | |
dc.identifier.orcid | 0000-0002-2177-2427 | |
dc.identifier.volume | 17 | |
dc.identifier.issue | 10 October | |
dc.identifier.startpage | e0275064 | |
dc.identifier.name-orcid | D’Arcy, Q | |
dc.identifier.name-orcid | Gharaee-Kermani, M; 0000-0002-2177-2427 | |
dc.identifier.name-orcid | Zhilin-Roth, A | |
dc.identifier.name-orcid | Macoska, JA | |
dc.working.doi | 10.7302/22168 | en |
dc.owningcollname | Internal Medicine, Department of |
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