IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation

IL-17 is a signature cytokine of Th17 cells, a recently described subset of effector CD4 T cells implicated in the development of several pathologies. We have examined the role of IL-17 in regulating endothelial NO synthase (eNOS) expression in human vascular endothelial cells (ECs) because of the key role of eNOS in determining the pathological outcome of immune-mediated vascular diseases. In cultured ECs, IL-17 increased expression of eNOS, eNOS phosphorylation at Ser1177, and NO production. The induction of eNOS expression by IL-17 was prevented by the pharmacological inhibition of NF-κB, MEK, and JNK, as well as by small interfering RNA-mediated gene silencing of these signaling pathways. The expression of IL-17 was then examined by immunohistochemistry in human arteries affected by transplant vasculopathy (TV), a vascular condition that is a leading reflection of chronic heart transplant rejection. IL-17 was expressed by infiltrating leukocytes in the intima of arteries with TV, and the majority of IL-17–positive cells were T cells. The number of IL-17–positive cells was not correlated with the intima/media ratio, but was negatively correlated with the amount of luminal occlusion. There was also a significant positive correlation between the number of IL-17–positive cells and the density of eNOS-expressing luminal ECs in arteries with TV. Altogether, these findings show that IL-17 induces the expression of eNOS in human ECs and that this may facilitate outward expansion of arteries afflicted with TV.

Section: Ascular Endothelial Cells (Ecs) Regulate Inflammatory Andmentioning

confidence: 99%

Induction of Endothelial Nitric Oxide Synthase Expression by IL-17 in Human Vascular Endothelial Cells: Implications for Vascular Remodeling in Transplant Vasculopathy

Liu

Lee

McManus

et al. 2012

“…Psoriatic skin lesions contain increased infiltrates of activated innate immune cells producing IL-23, which induces Th17 subset of T cells secreting IL-17A and IL-17F (4,5). These proinflammatory cytokines can activate keratinocytes and endothelial cells in the skin by binding to the IL-17 receptor, leading to development of skin inflammation and disease progression (6,7). Therefore, a number of biologic agents targeting the IL-23/Th17 pathway have demonstrated robust efficacy in the clinic and been approved recently for the treatment of moderate to severe plaque psoriasis (8)(9)(10).…”

mentioning

confidence: 99%

Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10

Zanin-Zhorov

Weiss

Trzeciak

et al. 2017

Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-α, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

“…The first step is the capture of inflammatory cells and their rolling on ECs via firmer adhesion to the ECs, followed by diapedesis and transvasation across the endothelium. This process is regulated by the expression of adhesion molecules on the endothelium in response to specific environmental stimuli, which is termed endothelial activation (39,40). In the current study, we investigated whether BFT activated the endothelium by inducing the expression of the adhesion molecule ICAM-1, which is necessary for monocyte adhesion.…”

Section: Discussionmentioning

confidence: 98%

Bacteroides fragilis Enterotoxin Upregulates Intercellular Adhesion Molecule-1 in Endothelial Cells via an Aldose Reductase-, MAPK-, and NF-κB–Dependent Pathway, Leading to Monocyte Adhesion to Endothelial Cells

Roh

Yoo

et al. 2011

Enterotoxigenic Bacteroides fragilis (ETBF) produces a ∼20-kDa heat-labile enterotoxin (BFT) that plays an essential role in mucosal inflammation. Although a variety of inflammatory cells is found at ETBF-infected sites, little is known about leukocyte adhesion in response to BFT stimulation. We investigated whether BFT affected the expression of ICAM-1 and monocytic adhesion to endothelial cells (ECs). Stimulation of HUVECs and rat aortic ECs with BFT resulted in the induction of ICAM-1 expression. Upregulation of ICAM-1 was dependent on the activation of IκB kinase (IKK) and NF-κB signaling. In contrast, suppression of AP-1 did not affect ICAM-1 expression in BFT-stimulated cells. Suppression of NF-κB activity in HUVECs significantly reduced monocytic adhesion, indicating that ICAM-1 expression is indispensable for BFT-induced adhesion of monocytes to the endothelium. Inhibition of JNK resulted in a significant attenuation of BFT-induced ICAM-1 expression in ECs. Moreover, inhibition of aldose reductase significantly reduced JNK-dependent IKK/NF-κB activation, ICAM-1 expression, and adhesion of monocytes to HUVECs. These results suggest that a signaling pathway involving aldose reductase, JNK, IKK, and NF-κB is required for ICAM-1 induction in ECs exposed to BFT, and may be involved in the leukocyte–adhesion cascade following infection with ETBF.