Ibuprofen regulation of microtubule dynamics in cystic fibrosis epithelial cells.
High-dose ibuprofen, an effective anti-inflammatory therapy for the treatment of cystic fibrosis (CF), has been shown to preserve lung function in a pediatric population. Despite its efficacy, few patients receive ibuprofen treatment due to potential renal and gastrointestinal toxicity. The mechanism of ibuprofen efficacy is also unclear. We have previously demonstrated that CF microtubules are slower to reform after depolymerization compared with respective wild-type controls. Slower microtubule dynamics in CF cells are responsible for impaired intracellular transport and are related to inflammatory signaling. Here, it is identified that high-dose ibuprofen treatment in both CF cell models and primary CF nasal epithelial cells restores microtubule reformation rates to wild-type levels, as well as induce extension of microtubules to the cell periphery. Ibuprofen treatment also restores microtubule-dependent intracellular transport monitored by measuring intracellular cholesterol transport. These effects are specific to ibuprofen as other cyclooxygenase inhibitors have no effect on these measures. Effects of ibuprofen are mimicked by stimulation of AMPK and blocked by the AMPK inhibitor compound C. We conclude that high-dose ibuprofen treatment enhances microtubule formation in CF cells likely through an AMPK-related pathway. These findings define a potential mechanism to explain the efficacy of ibuprofen therapy in CF.
Departments of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
Sharon M
SM
Rymut
Departments of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
Claire M
CM
Kampman
Departments of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
Deborah A
DA
Corey
Departments of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
Tori
T
Endres
Departments of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
Calvin U
CU
Cotton
Departments of Pediatrics, Case Western Reserve University, Cleveland, Ohio thomas.kelley@case.edu.
Thomas J
TJ
Kelley
D000107:Acetylation; D000263:Adenylate Kinase; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D008870:Microtubules / Q000378:metabolism*; D061251:Primary Cell Culture; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D000263:Adenylate Kinase; D007052:Ibuprofen
cystic fibrosis; ibuprofen; microtubule