Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines

作者：Zampell Jamie C; Avraham Tomer; Yoder Nicole; Fort Nicholas; Yan Alan; Weitman Evan S; Mehrara Babak J^*

来源：American Journal of Physiology - Cell Physiology, 2012, 302(2): C392-C404.

DOI：10.1152/ajpcell.00306.2011

• lymphangiogenesis
• vascular endothelial growth factor-C
• lymphedema
• transforming growth factor-beta 1
• interferon-gamma

Zampell JC, Avraham T, Yoder N, Fort N, Yan A, Weitman ES, Mehrara BJ. Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines. Am J Physiol Cell Physiol 302: C392-C404, 2012. First published September 21, 2011; doi:10.1152/ajpcell.00306.2011.-Lymphangiogenic cytokines such as vascular endothelial growth factor-C (VEGF-C) are critically required for lymphatic regeneration; however, in some circumstances, lymphatic function is impaired despite normal or elevated levels of these cytokines. The recent identification of anti-lymphangiogenic molecules such as interferon-gamma (IFN-gamma), transforming growth factor-beta 1, and endostatin has led us to hypothesize that impaired lymphatic function may represent a dysregulated balance in the expression of pro/anti-lymphangiogenic stimuli. We observed that nude mice have significantly improved lymphatic function compared with wild-type mice in a tail model of lymphedema. We show that gradients of lymphatic fluid stasis regulate the expression of lymphangiogenic cytokines (VEGF-A, VEGF-C, and hepatocyte growth factor) and that paradoxically the expression of these molecules is increased in wild-type mice. More importantly, we show that as a consequence of T-cell-mediated inflammation, these same gradients also regulate expression patterns of anti-lymphangiogenic molecules corresponding temporally and spatially with impaired lymphatic function in wild-type mice. We show that neutralization of IFN-gamma significantly increases inflammatory lymph node lymphangiogenesis independently of changes in VEGF-A or VEGF-C expression, suggesting that alterations in the balance of pro- and anti-lymphangiogenic cytokine expression can regulate lymphatic vessel formation. In conclusion, we show that gradients of lymphatic fluid stasis regulate not only the expression of pro-lymphangiogenic cytokines but also potent suppressors of lymphangiogenesis as a consequence of T-cell inflammation and that modulation of the balance between these stimuli can regulate lymphatic function.

• 出版日期2012-1