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Effect of Outer Hair Cell‐Specific STAT3 Deletion in the Noise‐induced Cellular Stress Response
Author(s) -
Dziennis Suzan,
Wilson Teresa L,
Foster Sarah L,
Nuttall Alfred L
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb142
Subject(s) - stat3 , stat protein , microbiology and biotechnology , cochlea , janus kinase 2 , biology , hair cell , janus kinase , chemistry , signal transduction , neuroscience
Background S ignal t ransducer and a ctivator of t ranscription 3 (STAT3) is part of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. STAT3 is activated by phosphorylation and translocates to the nucleus in response to inflammatory cytokines to induce a transcriptional response. Non‐canonical actions of STAT3 are becoming elucidated such as those effected in the cytoplasm and mitochondria. Loud sound exposure induces several stress responses including increased reactive oxygen species (ROS) which contribute to noise‐induced cochlear tissue damage. We previously reported the general JAK2/STAT3 inhibitor JSI‐124 reduced levels of ROS after noise exposure suggesting STAT3 contributes to noise‐induced cellular damage. Objective Here, we generated outer hair cell (OHC)‐specific STAT3 knock‐out mice to better understand the function of STAT3 in OHCs in response to cellular stress pathways induced after loud sound exposure. Methods and Results Floxed STAT3 mice were crossed with prestin‐CreER T2 mice for several generations to produce STAT3 fl/fl × prestin‐CreER T2+/− (STAT3 fl/fl ) mice. Tamoxifen treatment resulted in STAT3 deletion specifically in OHCs (STAT3 OHCΔ/Δ ). The OHCs of 8 week old STAT3 OHCΔ/Δ mice appeared morphologically normal and a full complement of OHCs was present. Ex vivo cochlea from STAT3 fl/fl and STAT3 OHCΔ/Δ mice were treated with IL‐6, antimycin A or corresponding vehicle followed by addition of the ROS detector CellROX. Nuclei were stained with Hoechst. IL‐6 or antimycin A treatment resulted in contrasting effects on nuclear morphology and ROS based on the loss of OHC‐specific STAT3, demonstrating the diverse contribution of STAT3 in the noise‐induced cellular stress response. Conclusions STAT3 either prevents or contributes to detrimental cellular stress pathways in OHCs. This may be due to multiple and diverse activities of STAT3 including both genomic actions as a transcription factor and non‐genomic actions such as interaction with the mitochondrial electron transport chain. Support or Funding Information Supported by grants 5R01DC000105 (ALN) and P30DC005983.