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Histones Activate Toll‐Like Receptor 9 to Trigger Calcium Oscillations in Rat Pancreatic Acinar Cells
Author(s) -
Cui Zong Jie,
Guo Hai Yan
Publication year - 2019
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.2019.33.1_supplement.719.9
Subject(s) - tlr9 , calcium , microbiology and biotechnology , endocrinology , medicine , chemistry , biology , biochemistry , gene expression , dna methylation , gene
In acute pancreatitis histones are released by infiltrating neutrophils, but how histones modulate pancreatic acinar cells has not been investigated. We have examined histone modulation of rat pancreatic acini and pancreatic acinar tumor cell AR4‐2J by calcium imaging. Histones were found to have no effect on calcium in pancreatic acini but blocked calcium oscillations induced by CCK or ACh. Both mixed (Hx) and individual (H1, H2A, H2B, H3, H4) histones induced calcium oscillations in AR4‐2J. RT‐PCR and Western blot verified expression of histone‐targeted TLR2, 4, 9. Immunocytochemistry identified TLR2/TLR4 on apical plasma membrane and TLR9 in zymogen granule regions in pancreatic acini. TLR2 was found on neighboring and TLR9 on peripheral plasma membranes but TLR4 was in nucleus in AR4‐2J clusters. Neither TLR2 agonist zymosan‐A nor TLR4 agonist lipopolysaccharide had any effect on calcium, but TLR9 agonist ODN1826 induced calcium oscillations; TLR9 antagonist ODN2088 blocked H4‐induced calcium oscillations in AR4‐2J, which also disappeared after treatment of AR4‐2J with glucocorticoid dexamethasone (Dex), with concurrent TLR9 migration from plasma membrane to cell interiors. TLR9 down regulation with siRNA completely suppressed H4‐induced calcium oscillations. These data together suggest that extracellular histones activate plasma membrane TLR9 to trigger calcium oscillations in AR4‐2J cells. TLR9 protein shuttling between plasma and endosomal membranes determines whether calcium signaling is triggered. Ongoing work will outline the signaling pathway from plasma membrane TLR9 activation to cytosolic calcium oscillations and its correlation with the canonical MyD88‐dependent pathway of TLR9 activation. Support or Funding Information This work was supported by The Natural Science Foundation of China (31670856). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .