Data from: Th2 cytokines inhibit lymphangiogenesis

Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC) proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2) cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4) and interleukin-13 (IL-13) have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis

Th2 cytokines inhibit lymphangiogenesis.

Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC) proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2) cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4) and interleukin-13 (IL-13) have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis

Inhibition of Inflammation and iNOS Improves Lymphatic Function in Obesity

xvii,1040 hlm

Raw Data

Raw dat

IL-4 or IL-13 blockade increases inflammatory lymphangiogenesis.

<p><b>A.</b> Representative gross images of corneas 14 days after suture placement. <b>B.</b> Representative immunofluorescent cornea whole mount images for LYVE-1. Scale bar = 100μm. <b>C.</b> Quantification of lymphatic vessel area per 0.25mm². Control vs. IL-4mAb (n = 8 in each; *p<0.001); control vs. IL-13mAb (n = 8 in each; *p<0.001); IL-4mAb vs. IL-13mAb (n = 8 in each; p = NS). <b>D.</b> Quantification of lymphatic vessel volume per 0.25mm². Control vs. IL-4mAb (n = 8 in each; *p<0.001); control vs. IL-13mAb (n = 8 in each; *p<0.001); IL-4mAb vs. IL-13mAb (n = 8 in each; *p<0.05).</p

IL-4 and IL-13 blockade does not increase corneal angiogenesis.

<p><b>A.</b> Representative immunofluorescent cornea whole mount images stained for CD31 and LYVE-1. Scale bar = 100μm. <b>B.</b> Quantification of blood vessel area per 0.25mm². Control vs. IL-4mAb (n = 8 in each; p = NS); control vs. IL-13mAb (n = 8 in each; p = NS); IL-4mAb vs. IL-13mAb (n = 8 in each; p = NS). <b>C.</b> Quantification of blood vessel volume per 0.25mm². Control vs. IL-4mAb (n = 8 in each; p = NS); control vs. IL-13mAb (n = 8 in each; p = NS); IL-4mAb vs. IL-13mAb (n = 8 in each; p = NS).</p

IL-4 and IL-13 blockade increases LEC proliferation <i>in vivo</i>.

<p><b>A.</b> Representative immunofluorescent cornea whole mount images stained for Ki67 and LYVE-1. Scale bar = 100μm. <b>B.</b> Quantification of Ki67⁺/LYVE-1⁺ cells (n/0.25mm²). Control vs. IL-4mAb (n = 5 in each; *p<0.01); control vs. IL-13mAb (n = 5 in each; *p<0.01); IL-4mAb vs. IL-13mAb (n = 5 in each; *p<0.01).</p