TUMOR NECROSIS FACTOR ALPHA (TNFα) INDUCTION OF THYMUS AND ACTIVATION REGULATED CHEMOKINE (TARC) EXPRESSION IS MEDIATED BY 15-LIPOXYGENASE 15-(LOX)-2 IN THE EPIAIRWAY™ HUMAN TRACHEAL/BRONCHIAL EPITHELIAL MODEL.
RATIONALE: T-Helper 2-type (TH2) T cells play a predominant role in human airway inflammation and asthma. TARC, a specific chemoattractant for TH2 cells, is induced by TNFα treatment of human airway cells, however, the cellular pathways involved in mediating TARC induction by TNFα are not fully understood. METHODS: Researchers at the Vanderbilt University School of Medicine and MatTek Corp. used the EpiAirway™ in vitro human tracheal/bronchial epithelial model to study expression of TARC, 15-LOX-1 and 15-LOX-2 following treatment with TNFα, interferon-γ (INFγ), interleukin-4 (IL-4), IL-13 or various combinations of these cytokines. Western blotting, ELISA and RT-PCR were utilized to analyze protein and mRNA expression. RESULTS: Treatment of EpiAirway tissues with TNFα or IL-13 significantly induced TARC protein secretion by EpiAirway. The LOX inhibitor nordihydroguairetic acid blocked TNFα or IL-13 induced TARC secretion. INFγ also caused a slight induction of TARC protein secretion. RT-PCR revealed that constitutive expression of 15-LOX-1 was enhanced by IL-4 and IL-13. Additionally, TNFα was found to induce expression of 15-LOX-2 message and protein, while INFγ inhibited the TNFα-induced increase in both message and protein. CONCLUSIONS: Induction of TARC by TNFα and IL-13 is mediated by 15-LOX-2 and possibly 15-LOX-1, but the effect of INFγ appears to be mediated by an alternate pathway. These results provide a link between TNFα, 15-LOX-2 and TARC and may help to explain how TNFα functions to promote human airway inflammation in allergy and asthma.
15-LOX-1, 15-LOX-2, 15-Lipoxygenase, Airway, Asthma, Bronchial, Chemoattractant, Cytokines, ELISA, EpiAirway, Gene expression, IL-13, IL-4, INF-gamma, Inflammation, Interferon gamma, Interleukin 4, LOX, Messenger RNA (mRNA), NHBE, Nordihydroguairetic acid, Normal human tracheal/bronchial epithelial model, RT-PCR, T-Helper 2-type T cells, TARC, TH2, TNF-a, Tracheal, Tumor necrosis factor alpha, Western blotting
Request a copy of this paper, click here.