Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1.
The concept of inflammation-induced lymphangiogenesis (ie, formation of new lymphatic vessels) has long been recognized, but the molecular mechanisms remained largely unknown. The 2 primary mediators of lymphangiogenesis are vascular endothelial growth factor receptor-3 (VEGFR-3) and Prox1. The key factors that regulate inflammation-induced transcription are members of the nuclear factor-kappaB (NF-kappaB) family; however, the role of NF-kappaB in regulation of lymphatic-specific genes has not been defined. Here, we identified VEGFR-3 and Prox1 as downstream targets of the NF-kappaB pathway. In vivo time-course analysis of inflammation-induced lymphangiogenesis showed activation of NF-kappaB followed by sequential up-regulation of Prox1 and VEGFR-3 that preceded lymphangiogenesis by 4 and 2 days, respectively. Activation of NF-kappaB by inflammatory stimuli also elevated Prox1 and VEGFR-3 expression in cultured lymphatic endothelial cells, resulting in increased proliferation and migration. We also show that Prox1 synergizes with the p50 of NF-kappaB to control VEGFR-3 expression. Collectively, our findings suggest that induction of the NF-kappaB pathway by inflammatory stimuli activates Prox1, and both NF-kappaB and Prox1 activate the VEGFR-3 promoter leading to increased receptor expression in lymphatic endothelial cells. This, in turn, enhances the responsiveness of preexisting lymphatic endothelium to VEGFR-3 binding factors, VEGF-C and VEGF-D, ultimately resulting in robust lymphangiogenesis.
Flister
Michael J
MJ
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794-9626, USA.
Wilber
Andrew
A
Hall
Kelly L
KL
Iwata
Caname
C
Miyazono
Kohei
K
Nisato
Riccardo E
RE
Pepper
Michael S
MS
Zawieja
David C
DC
Ran
Sophia
S
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D013997:Time Factors; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D000098551:Prospero-Related Homeobox 1 Protein; C467483:vascular endothelial growth factor C, mouse; C073701:Nfkb1 protein, mouse; D040321:Vascular Endothelial Growth Factor Receptor-3