Interleukin-17 promotes angiogenesis and tumor growth.
Interleukin-17 (IL-17) is a CD4 T-cell-derived proinflammatory cytokine. We investigated the effects of locally produced IL-17 by tumors as a means to evaluate its biologic function. Although recombinant IL-17 protein or retroviral transduction of IL-17 gene into tumors did not affect in vitro proliferation, IL-17 transfectants grew more rapidly in vivo when compared with controls. Immunostaining for Factor VIII revealed that tumors transduced with IL-17 had significantly higher vascular density when compared with controls. IL-17 indeed elicited neovascularization in rat cornea. In addition, angiogenic activity present in the conditioned media of CD4 T cells was markedly suppressed by neutralizing monoclonal antibody to IL-17. IL-17 had no direct effect on the growth of vascular endothelial cells, whereas IL-17 significantly stimulated migration. IL-17 also markedly promoted the cord formation of vascular endothelial cells. In addition, IL-17 up-regulated elaboration of a variety of proangiogenic factors by fibroblasts as well as tumor cells. These findings reveal a novel role for IL-17 as a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and cord formation and regulates production of a variety of proangiogenic factors. Furthermore, they suggest that inhibition of biologic action of IL-17 may have therapeutic benefits when applied to angiogenesis-related disorders.
Numasaki
Muneo
M
Department of Surgery, School of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, PA, USA. numasaki77@aol.com
Fukushi
Jun-ichi
J
Ono
Mayumi
M
Narula
Satwant K
SK
Zavodny
Paul J
PJ
Kudo
Toshio
T
Robbins
Paul D
PD
Tahara
Hideaki
H
Lotze
Michael T
MT
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000209:etiology / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D051381:Rats; D014161:Transduction, Genetic; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects
D006133:Growth Substances; D020381:Interleukin-17