T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma

Abstract

IL-25 (IL-17E) is a T-helper cell type 2 (Th2) cytokine best described as a potentiator of Th2 memory responses. Reports of expression of its receptor, IL-25R, on airways structural cells suggest a wider role for IL-25 in remodeling. We hypothesized that IL-25 stimulates local angiogenesis in the asthmatic bronchial mucosa. Immunoreactive IL-25 + , IL-25R + , and CD31 + (endothelial) cells in sections of bronchial biopsies from asthmatics and controls were detected by immunohistochemistry. The effect of IL-25 on angiogenesis was examined using an in vitro assay. Real-time PCR was used to detect expression of IL-25R and VEGF mRNA in cultured human vascular endothelial cells (HUVEC), and a cell proliferation kit (WST-8) was used to measure the effect of IL-25 on HUVEC proliferation. Immunostaining showed that IL-25 + , IL-25R + , and CD31 + /IL-25R + cells were significantly elevated in the bronchial mucosa of asthmatics compared with controls (P < 0.003). In asthmatics, the numbers of IL-25 + cells correlated inversely with the forced expiratory volume in 1 s (r = −0.639; P = 0.01). In vitro, HUVEC constitutively expressed IL-25R, which was up-regulated further by TNF-α. IL-25 and TNF-α also increased expression of VEGF and VEGF receptors. IL-25 increased HUVEC proliferation and the number, length, and area of microvessel structures in a concentration-dependent manner in vitro. VEGF blockade, the PI3K-specific inhibitor LY294002, and the MAPK/ERK1/2 (MEK1/2)-specific inhibitor U0126 all markedly attenuated IL-25-induced angiogenesis, and the inhibitors also reduced IL-25-induced proliferation and VEGF expression. Our findings suggest that IL-25 is elevated in asthma and contributes to angiogenesis, at least partly by increasing endothelial cell VEGF/VEGF receptor expression through PI3K/Akt and Erk/MAPK pathways.

A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells

“…On the other hand, IL-17E/IL-25 is also an angiogenic stimulator, which signals through heterodimeric receptor complex composed of IL-17RA and IL-17RB. Unlike IL-17A and IL-17A/F, IL-17E/IL-25 has the ability to promote the growth of vascular endothelial cells in a concentration-dependent manner (Corrigan et al 2011). Conversely, IL-17B and IL-17F negatively regulates angiogenesis through inhibition of migration and/or capillary tube formation of vascular endothelial cells (Sanders et al 2010).…”

“…In addition, to define which signaling pathway(s) is involved in IL-17A/F-induced capillary-like endothelial tube formation in a co-culture system of HUVECs and HDFs, specific inhibitor to PI3K (LY294002), ERK (PD98059) or JNK (SP600125) (10.0 μM for the first 3 days, followed by 2.0 μM until the end of the 11-day culture period) was added (Saito et al 2003;Corrigan et al 2011).…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…156 IL-17E also contributes to VEGF signaling-induced angiogenesis via the Erk/MAPK and PI3K/Akt pathways in asthma. 157 Moreover, blocking IL-17E in the airways of allergenFunctional mechanisms of IL-17 family cytokines X Song et al challenged mice decreases the deposition of peribronchial collagen and the hyperplasia of airway smooth muscles. 158 IL-17E contributes to allergenic resources by orchestrating airway remodelling in addition to inducing airway type 2 inflammation.…”

T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

“…3), many of which have critical functions in airway allergy. For example, Trim24-deficient T cells had reduced expression of Ccl1 and Ccl5, chemokines involved in the recruitment of eosinophils (62) and T H 2 cells (63), respectively; reduced expression of Il4, Il21, and Spp1 (Osteopontin), all of which contribute significantly to airway allergy (64)(65)(66); and reduced expression of Il1rl1 (Il33r) and il17re (Il25r), both of which contribute to T H 2 cell activation and recruitment (67)(68)(69). These data highlight the importance of Trim24 for T H 2 cell effector function and provide multiple mechanistic explanations for the reduced airway allergy observed in mice with Trim24 −/− T cells.…”