Conditional regulation of cyclooxygenase-2 in tracheobronchial epithelial cells modulates pulmonary immunity.
Cyclooxygenase-2 (COX-2) gene expression in the lung is induced in pathological conditions such as asthma and pneumonia; however, the exact impact of COX-2 gene expression in the airway in regulating inflammatory and immunological response in the lung is not understood. To define a physiological role of inducible COX-2 in airway epithelial cells, we developed a novel line of transgenic mice, referred to as CycloOxygenase-2 TransActivated (COTA) mice, that overexpress a COX-2 transgene in the distribution of the CC-10 promoter in response to doxycycline. In response to doxycycline treatment, COX-2 expression was increased in airway epithelium of COTA mice and whole lung tissue contained a three- to sevenfold increase in prostaglandin E(2) (PGE(2)), prostaglandin D(2) (PGD(2)) thromboxane B(2) (TXB(2)) and 6-Keto prostaglandin F(2alpha) (PGF(2alpha)) compared to wild-type and untreated COTA mice. Interestingly, primary mouse tracheal epithelial cells from COTA mice produced only PGE(2) by doxycycline-induced COX-2 activation, providing an indication of cellular specificity in terms of mediator production. In the ovalbumin model, in which doxycycline was given at the sensitization stage, there was an increase in interleukin (IL)-4 level in lung tissue from COTA mice compared to untreated COTA and wild-type mice. In addition, COTA mice that were treated with doxycycline had impaired clearance of Pseudomonas aeruginosa pneumonia compared to wild-type mice. COX-2 gene expression in airway epithelial cells has an important role in determining immunological response to infectious and allergic agents.
Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois, Chicago, IL, USA.
G Y
GY
Park
N
N
Hu
X
X
Wang
R T
RT
Sadikot
F E
FE
Yull
M
M
Joo
R S
RS
Peebles
T S
TS
Blackwell
J W
JW
Christman
D000818:Animals; D001980:Bronchi / Q000201:enzymology* / Q000276:immunology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology*; D015232:Dinoprostone / Q000096:biosynthesis; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D005838:Genotype; D018928:Immunity, Mucosal; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D011453:Prostaglandins / Q000096:biosynthesis; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000254:growth & development; D020545:Respiratory Mucosa / Q000276:immunology*; D014132:Trachea / Q000201:enzymology* / Q000276:immunology
D011453:Prostaglandins; D015847:Interleukin-4; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone