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PKC‐δ Mediates Sphk2 Activation And Histone Acetylation In Pseudomonas aeruginosa ‐Induced Lung Inflammation
Author(s) -
Ebenezer David Lenin,
Fu Panfeng,
Ha Alison WingZi,
Natarajan Viswanathan
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.629.27
Subject(s) - sphingosine , sphingosine kinase 1 , phosphorylation , protein kinase c , inflammation , microbiology and biotechnology , kinase , gene silencing , cancer research , biology , histone , chemistry , sphingosine 1 phosphate , immunology , biochemistry , receptor , gene
Pseudomonas aeruginosa (PA), a gram‐negative opportunistic pathogen, the leading cause of inflammation‐driven gradual deterioration of the lung function among cystic fibrotic patients, also causes pneumonia in immunosuppressed and mechanically ventilated patients. Our research intends to understand the role of nuclear Sphingolipids in modifying the epigenetic landscape in PA–induced lung inflammation. Previously, we have shown that Sphingosine kinase 2 (SphK2) generated nuclear Sphingosine‐1‐Phospahate (S1P), a simple bioactive sphingolipid, is an epigenetic co‐regulator of PA‐induced lung inflammation, as evident from our murine model and in vitro studies. Recently, we have identified a novel role of Protein Kinase C‐δ (PKC‐δ) in mediating the PA‐induced phosphorylation of Sphingosine Kinase 2 and histone acetylation. Mouse alveolar Type 2 cells challenged with PA induced phosphorylation of PKC‐δ (S 299), which is necessary for its activation and subsequent translocation to nucleus. PA‐induced activation of PKC‐δ also stimulated nuclear SphK2 phosphorylation in mouse lung type II cells. The PKC inhibitor, bisindolylmaleimide, blocked PA‐induced Histone H3 & H4 acetylation in mouse lung epithelial cell line (MLE‐12). Further, PA‐induced SphK2 phosphorylation and histone acetylation was blocked by small interfering RNA (siRNA) silencing of PKC‐δ in MLE‐12 cells. PA‐induced PKC‐δ activation also resulted in elevated mRNA expression of inflammatory cytokines, IL‐6 and TNF‐α, which was decreased significantly by overexpression of adenoviral dominant negative PKC‐δ mutant in MLE‐12 cells, suggesting a key role for PKC‐δ in regulating inflammatory cytokines. Furthermore, use of dominant negative PKC‐δ mutant also suppressed PA‐induced IL‐6 secretion, suggesting the secondary effector role of PKC‐δ in regulating SphK2 mediated down stream expression of inflammatory cytokines. These studies underscore the role of PKC‐δ in regulating PA‐induced inflammation via SphK2 phosphorylation, and increased histone acetylation suggesting that targeting PKC‐δ could ameliorate the bacterial inflammation of the lung. Support or Funding Information This work was supported by NIH P01 HL 98050 to VN