title: Thromboxane A2 Regulates CXCL1 and CXCL8 Chemokine Expression in the Nasal Mucosa-Derived Fibroblasts of Chronic Rhinosinusitis Patients.
abstract: BACKGROUND
  Chronic rhinosinusitis without nasal polyps (CRSsNP) is a common chronic disease and the etiology remains unclear. Thromboxane A2 (TXA2) participates in platelet aggregation and tissue inflammation. In this study, the CXCL1/8 chemokine and TXA2-TP receptor expression in the CRSsNP mucosa was investigated.
  
  
  METHODS
  Immunohistochemistry, chemokine release assay by ELISA, RT-PCR, Real-time PCR, Western blotting, pharmacological and siRNA knockdown analysis were applied in the CRSsNP tissue specimen and cultured nasal mucosa-derived fibroblasts.
  
  
  RESULTS
  The immunohistochemistry results indicated that CXCL1 and CXCL8 were highly expressed in the CRSsNP mucosa compared with the controls; however, the TP receptors were expressed in both mucosa. Therefore, U46619 and IBOP, a TXA2 analog and TP agonist, were used to explore the role of TP activation in CXCL1/8 expression; both of these induced CXCL1/8 mRNA and protein expression in CRSsNP mucosa-derived fibroblasts. U46619 phosphorylated PI-3K, cyclic AMP (cAMP)/PKA, PKC, and cAMP response element (CREB). Activation of cAMP/PKA, PKC, and CREB was the major pathway for cxcl1/8 gene transcription. Pharmacological and siRNA knockdown analyses revealed that activation of cAMP/PKA and PKCμ/PKD pathways were required for CREB phosphorylation and PKA/C crosstalked with the PI-3K pathway.
  
  
  CONCLUSIONS
  Our study provides the first evidence for abundant TP receptor and CXCL1/8 expression in human CRSsNP mucosa and for TXA2 stimulation inducing CXCL1/8 expression in nasal fibroblasts primarily through TP receptor, cAMP/PKA, PKCμ/PKD, and CREB-related pathways.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.|Department of Chemistry, Graduate Institute of Applied Science and Engineering, College of Science and Engineering, Fu-Jen Catholic University, Taipei, Taiwan.|Graduate Institute of Basic Medicine, Fu-Jen Catholic University, Taipei, Taiwan.|School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan.
authors.forename: Yih-Jeng
authors.initials: YJ
authors.lastname: Tsai
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.|School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan.
authors.forename: Sheng-Po
authors.initials: SP
authors.lastname: Hao
authors.affiliation: School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Chen
authors.affiliation: School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Wu
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D009297:Nasal Mucosa / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000378:metabolism; D012220:Rhinitis / Q000378:metabolism* / Q000473:pathology; D015290:Second Messenger Systems; D012852:Sinusitis / Q000378:metabolism* / Q000473:pathology; D013928:Thromboxane A2 / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D054360:Chemokine CXCL1; D017362:Cyclic AMP Response Element-Binding Protein; D005231:Fatty Acids, Unsaturated; D016209:Interleukin-8; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C