Th2 Cytokines Inhibit Lymphangiogenesis

Abstract

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.

Obesity, But Not High Fat Diet, Impairs Lymphatic Function

“…50,51 Finally, T cell-derived cytokines including IFN-γ, IL-4 and IL-13 have been shown to directly inhibit lymphangiogenesis. 46,52 Consistent with previous studies in obese mice and patients, 26 we noted a marked increase in VEGF-C expression in tissues and serum harvested from obese HFD-fed C57BL/6J mice. This effect has a key role on glucose homeostasis in obesity by regulating macrophage infiltration and differentiation.…”

“…45,46 Thus, it may seem contradictory that we found decreased lymphatic vessel density in obese animals in which we also noted marked subcutaneous infiltration of T cells and macrophages. However, numerous other studies have shown that chronic inflammation in some physiologic settings can markedly inhibit lymphangiogenesis 47,48 and that the initial lymphangiogenic response to acute inflammation subsides over time.…”

Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedema

“…Indeed, previous studies have shown that radiation-induced fibrosis markedly decreases interstitial fluid transport and that inhibition of fibrosis effectively preserves lymphatic function independent of LEC survival in this setting (53). Finally, a number of recent studies have shown that T cells are potently antilymphangiogenic and that this effect is mediated, at least in part, by the expression of inflammatory cytokines such as IFN-γ, IL-4, and IL-13 (54)(55)(56). The findings of the current study are consistent with these studies, since we found that depletion of CD4 + cells increased LVD histologically and radiographically.…”

The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

“…Interestingly, in mice we have observed lymphatic vessels running deeply inside the WAT in visceral fat depots and close to a blood vessel (Figure 2). On the other hand, a large number of studies have shown that inflammation increases lymphangiogenesis (Kataru et al, 2009; Savetsky et al, 2015b); therefore, it is possible that once a certain "threshold" of obesity is overcome, this obesity (through inflammation) compromises the function of the lymphatic vasculature. This would explain why only certain obese patients have defective lymphatic drainage in which severely obese individuals with a BMI greater than 59 have lower extremity lymphedema, whereas obese patients with a BMI between 30 and 53 had normal lower extremity lymphatic function (Greene et al, 2012).…”