IL-10 inhibits endothelium-dependent T cell costimulation by up-regulation of ILT3/4 in human vascular endothelial cells.
ABSTRACT Effects of IL-10 on endothelium-dependent T cell activation have not been investigated in detail. We confirm expression of the IL-10 receptor and effective signaling via STAT-3 in human umbilical vein endothelial cells (HUVEC). In CD4 T cell cocultures with HUVEC, pretreatment of endothelial cells with IL-10 resulted in significant dose-dependent inhibition of CD4 T cell proliferation, which also occurred when IL-10 was removed after pretreatment before starting cocultures. Th1/Th2 polarization of proliferated T cells, endothelial nitric oxide (NO), or IL-12 production were unchanged. However, IL-10 stimulation resulted in up-regulation of SOCS-3, a negative regulator of cytokine secretion, and induction of the inhibitory surface molecules immunoglobulin-like transcript 3 and 4 (ILT3/ILT4) in EC, potentially involving glucocorticoid-induced leucine zipper (GILZ). Addition of blocking antibodies against ILT3/ILT4 to EC/T cell cocultures resulted in nearly complete reestablishment of T cell proliferation. In contrast, addition of soluble ILT3 or overexpression of ILT3 in cocultures significantly reduced T cell proliferation. No induction of foxp3+ regulatory T cells was seen. In conclusion, the T cell costimulatory potential of human EC is markedly suppressed by IL-10 due to up-regulation of ILT3/ILT4, obviously not involving generation of Treg. This identifies a novel action of IL-10 in EC and a potential therapeutical target for local immunomodulation.
SourceAvailable from: Zhongjian Cheng[Show abstract] [Hide abstract]
ABSTRACT: Endothelial dysfunction is a pathological status of the vascular system, which can be broadly defined as an imbalance between endothelium-dependent vasoconstriction and vasodilation. Endothelial dysfunction is a key event in the progression of many pathological processes including atherosclerosis, type II diabetes and hypertension. Previous reports have demonstrated that pro-inflammatory/immunoeffector cytokines significantly promote endothelial dysfunction while numerous novel anti-inflammatory/immunosuppressive cytokines have recently been identified such as interleukin (IL)-35. However, the effects of anti-inflammatory cytokines on endothelial dysfunction have received much less attention. In this analytical review, we focus on the recent progress attained in characterizing the direct and indirect effects of anti-inflammatory/immunosuppressive cytokines in the inhibition of endothelial dysfunction. Our analyses are not only limited to the importance of endothelial dysfunction in cardiovascular disease progression, but also expand into the molecular mechanisms and pathways underlying the inhibition of endothelial dysfunction by anti-inflammatory/immunosuppressive cytokines. Our review suggests that anti-inflammatory/immunosuppressive cytokines serve as novel therapeutic targets for inhibiting endothelial dysfunction, vascular inflammation and cardio- and cerebro-vascular diseases.Journal of Hematology & Oncology 10/2014; 7(1):80. DOI:10.1186/s13045-014-0080-6 · 4.93 Impact Factor
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ABSTRACT: Solid organ transplantation is the only treatment for end-stage organ failure but this life-saving procedure is limited by immune-mediated rejection of most grafts. Blood vessels within transplanted organs are targeted by the immune system and the resultant vascular damage is a main contributor to acute and chronic graft failure. The vasculature is a unique tissue with specific immunological properties. This review discusses the interactions of the immune system with blood vessels in transplanted organs and how these interactions lead to the development of transplant arteriosclerosis, a leading cause of heart transplant failure.Frontiers in Immunology 01/2014; 5:684. DOI:10.3389/fimmu.2014.00684
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ABSTRACT: Immunoglobulin-like transcript (ILT) 3 and 4 are inhibitory receptors that modulate immune responses. Their expression has been reported to be affected by interferon, offering a possible mechanism by which this cytokine exerts its therapeutic effect in multiple sclerosis, a condition thought to involve excessive immune activity. To investigate this possibility, we measured expression of ILT3 and ILT4 on immune cells from multiple sclerosis patients, and in post-mortem brain tissue. We also studied the ability of interferon beta, alone or in combination with vitamin D, to induce upregulation of these receptors in vitro, and compared expression levels between interferon-treated and untreated multiple sclerosis patients. In vitro interferon beta treatment led to a robust upregulation of ILT3 and ILT4 on monocytes, and dihydroxyvitamin D3 increased expression of ILT3 but not ILT4. ILT3 was abundant in demyelinating lesions in postmortem brain, and expression on monocytes in the cerebrospinal fluid was higher than in peripheral blood, suggesting that the central nervous system milieu induces ILT3, or that ILT3 positive monocytes preferentially enter the brain. Our data are consistent with involvement of ILT3 and ILT4 in the modulation of immune responsiveness in multiple sclerosis by both interferon and vitamin D.PLoS ONE 12/2014; 9(12):e115488. DOI:10.1371/journal.pone.0115488 · 3.53 Impact Factor