In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis.
OBJECTIVE
Interleukin-13 (IL-13) is a pleiotropic cytokine that can affect vessel formation, an important component of the rheumatoid arthritis (RA) synovial tissue pannus. The purpose of this study was to use a gene therapy approach to investigate the role of IL-13 in angiogenesis in vivo, using a rat adjuvant-induced arthritis model of RA.


METHODS
Ankle joints of female rats were injected preventatively with an adenovirus vector containing human IL-13 (AxCAIL-13), a control vector with no insert (AxCANI), or phosphate buffered saline (PBS). Joints were harvested at the peak of arthritis, and histologic and biochemical features were evaluated.


RESULTS
AxCAIL-13-treated joint homogenates had lower hemoglobin levels, suggesting reduced joint vascularity, and both endothelial cell migration and tube formation were significantly inhibited (P < 0.05). Similarly, AxCAIL-13 inhibited capillary sprouting in the rat aortic ring assay and vessel growth in the Matrigel plug in vivo assay. IL-13 gene delivery resulted in up-regulation and association of phosphorylated ERK-1/2 and protein kinase Calpha/betaII, suggesting a novel pathway in IL-13-mediated angiostasis. The angiostatic effect of AxCAIL-13 was associated with down-regulation of proangiogenic cytokines (IL-18, cytokine-induced neutrophil chemoattractant 1/CXCL1, lipopolysaccharide-induced CXC chemokine/CXCL5) and up-regulation of the angiogenesis inhibitor endostatin. The expression and activity of matrix metalloproteinases 2 and 9, which participate in angiogenesis, was impaired in response to IL-13 as compared with AxCANI and PBS treatment.


CONCLUSIONS
Our findings support a role for IL-13 as an in vivo antiangiogenic factor and provide a rationale for its use in RA to control pathologic neovascularization.
Haas
Christian S
CS
University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
Amin
M Asif
MA
Ruth
Jeffrey H
JH
Allen
Brittany L
BL
Ahmed
Salahuddin
S
Pakozdi
Angela
A
Woods
James M
JM
Shahrara
Shiva
S
Koch
Alisa E
AE
D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000628:therapy*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy; D006454:Hemoglobins / Q000032:analysis; D006614:Hindlimb; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics* / Q000378:metabolism; D007596:Joints / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014020:Tissue Extracts / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D006454:Hemoglobins; D018793:Interleukin-13; D014020:Tissue Extracts; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9