The Role of Tumor Necrosis Factor-alpha and Interferon-gamma in Regulating Angiomotin-Like Protein 1 Expression in Lung Microvascular Endothelial Cells

作者：Nakajima Yoshio; Nakamura Yutaka^*; Shigeeda Wataru; Tomoyasu Makoto; Deguchi Hiroyuki; Tanita Tatsuo; Yamauchi Kohei

来源：Allergology International, 2013, 62(3): 309-322.

DOI：10.2332/allergolint.12-OA-0528

• angiogenesis
• angiomotin
• angiomotin-like protein 1
• COPD
• emphysema

Background: Angiogenesis in the alveolar septa is thought be a critical factor in pulmonary emphysema. Angiomotin-like protein 1 (AmotL1) is involved in angiogenesis via regulating endothelial cell function. However, the role of AmotL1 in the pathogenesis of pulmonary emphysema has not been elucidated. The objective of this study is to evaluate the expression of AmotL1 in lung tissues from a murine model with emphysema, as well as from patients with chronic obstructive pulmonary disease (COPD). Furthermore, we analyzed the regulation of AmotL1 expression by TNF-alpha and IFN-gamma in endothelial cells in vitro.
Methods: Nrf2 knockout mice were exposed to cigarette smoke (CS) for 4 weeks, and the down-regulated genes affecting vascularity in the whole lung were identified by microarray analysis. This analysis revealed that the mRNA expression of AmotL1 decreased in response to CS when compared with air exposure. To confirm the protein levels that were indicated in the microarray data, we determined the expression of AmotL1 in lung tissues obtained from patients with COPD and also determined the expression of AmotL1, NR kappa B and I kappa B alpha in cultured normal human lung microvascular endothelial cells (HLMVECs) that were stimulated by TNF-alpha and IFN-gamma.
Results: We found that the number of AmotL1-positive vessels decreased in the emphysema lungs compared with the normal and bronchial asthmatic lungs. IFN-gamma pretreatment diminished the TNF-alpha-induced AmotL1 in the cultured HLMVECs by blocking the degradation of I kappa B alpha.
Conclusions: These results suggested that IFN-gamma exhibits anti-angiogenesis effects by regulating the expression of TNF-alpha-induced AmotL1 via NF kappa B in emphysema lungs.

• 出版日期2013-9