The aryl hydrocarbon receptor is a regulator of cigarette smoke induction of the cyclooxygenase and prostaglandin pathways in human lung fibroblasts.
Cigarette smoking can lead to chronic lung inflammation and lung cancer. Chronic inflammation, associated with expression of cyclooxygenase-2 (COX-2) and prostaglandins, predisposes to malignancy. We recently demonstrated that human lung fibroblasts are activated by cigarette smoke to express COX-2 and prostaglandin E(2) (PGE(2)). Little is known about the mechanism whereby smoke activates human lung fibroblasts to produce proinflammatory mediators. Herein, we report the central role of the aryl hydrocarbon receptor (AHR) in cigarette smoke extract (CSE)-induced COX-2, microsomal PGE(2) synthase (mPGES), and PGE(2) production in human lung fibroblasts. Western blot analysis revealed that primary strains of human lung fibroblasts express AHR and aryl hydrocarbon nuclear translocator protein, supporting the possibility that smoke activates lung fibroblasts through this pathway. Experiments were subsequently performed to determine whether the AHR was activated by CSE. Immunocytochemistry and EMSA analysis revealed that CSE induced nuclear translocation of the AHR in human lung fibroblasts. CSE decreased protein levels of the AHR, consistent with AHR ligand-induced proteosome-mediated degradation. CSE also induced mPGES-1 and COX-2 protein and increased PGE(2) production. Treatment of human fibroblasts with AHR antagonists in the presence of CSE inhibited AHR nuclear translocation as well as COX-2, mPGES-1, and PGE(2) production. These data indicate that the AHR pathway plays an important role in cigarette smoke-mediated COX-2 and PG production in human lung fibroblasts and may contribute to tobacco-associated inflammation and lung disease.
Martey
C A
CA
Chemistry Department, Shippensburg University, Pennsylvania, USA.
Baglole
C J
CJ
Gasiewicz
T A
TA
Sime
P J
PJ
Phipps
R P
RP
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D012906:Smoke; D014157:Transcription Factors / Q000378:metabolism; D014026:Nicotiana
C503867:3',5'-dimethoxyflavone; C503868:3'-dimethylaminoflavone; C091768:3'-methoxy-4'-nitroflavone; C497396:ARNT protein, human; D004268:DNA-Binding Proteins; D047309:Flavones; D005419:Flavonoids; D008565:Membrane Proteins; D018336:Receptors, Aryl Hydrocarbon; D012906:Smoke; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone