Interleukin-17 Stimulates STAT3-Mediated Endothelial Cell Activation for Neutrophil Recruitment

Abstract

Background/Aims: Interleukin-17 (IL-17) is a major pro-inflammatory cytokine that initiates and maintains inflammation. However, the molecular mechanisms as to how IL-17 influences endothelial cells to promote neutrophil recruitment are not fully understood. Methods: Human endothelial cells (HMECs) were stimulated with IL-17, and investigated for proliferation, migration, and tubule formation activities. Transwell chemotaxis and adhesion assays were performed to assess neutrophil recruitment. Cytokine production was measured by Cytokine Array Chip and ELISA. Western blotting and immunofluorescent analysis were used to detect the phosphorylation and translocation of STAT3. Specific inhibitors, small interfering RNA, and phosphorylation mutants were used to confirm that IL-17 induced STAT3 activation via IL-17RA signaling. Results: Activation of HMECs with IL-17 induced STAT3 phosphorylation and nuclear translocation, which were associated with induction of GRO-α, GM-CSF and IL-8, and neutrophil recruitment. Phosphorylation of STAT3 was identified mainly at the tyrosine in position 705 (Y705), and the Y705F mutants attenuated IL-17-mediated STAT3 activation. Moreover, specific inhibitors, FLLL31, or siRNA silencing of STAT3 attenuated HMECs activation, resulting in inhibition of GRO-α, GM-CSF, IL-8 production, and neutrophil recruitment. Furthermore, phosphorylation of STAT3 was identified as downstream of IL-17RA signaling. Conclusions: IL-17 induced STAT3 activation as a necessary step in endothelial cell activation and neutrophil recruitment.

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

“…Concerning the angiogenic role of IL-17A in psoriasis, it is important to emphasize the direct effect of this cytokine on the proliferation of IL-17R-bearing ECs, as previously reported [14,17] and confirmed in this study. At the molecular level, we observe that IL-17A supports EC proliferation by inducing activation of either NF-κB-, ERK1/2- or STAT3-dependent pathways, known to be implicated in proliferation and survival of several cell types.…”

“…In human dermal microvascular ECs (HDMECs), IL-17A cooperates with TNF-α in the induction of CSF1/G-CSF and CXCL1/GRO-α [14], whereas in brain ECs IL-17A alone stimulates the release of CCL2/MCP-1 and CXCL1/GRO-α [16]. On an immortalized endothelial cell line, IL-17A was able to stimulate the release of CXCL1/GRO-α, CSF2/GM-CSF and CXCL8/IL-8 [17]. Therefore, literature data are highly variable, considering the different origin of the utilized ECs and the diverse culture conditions.…”

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

“…The wounds between the edges of the scratch were measured for quantitative analysis of cell migration. Wound width = wound area/wound high in each group [24]. …”

Regulatory T cells and T helper 17 cells in viral infection

“…Th17 cells could aggravate inflammatory responses by promoting the recruitment of inflammatory cells and increasing the expression of pro‐inflammatory cytokines, ultimately leading to liver damage . Intrahepatic and peripheral Th17 cells and the serum concentration of IL‐17 were all significantly elevated in patients with CHB and HBV‐associated acute and chronic liver failure (ACLF) than asymptomatic chronic HBV carriers (AsC) and normal controls.…”