IFNγ‐responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down‐regulation of Dll4

Abstract

Although IFNγ is regarded as a key cytokine in angiostatic response, our poor understanding of its effective cellular target drastically limits its clinical trials against angiogenesis-related disorders. Here, we investigated the effect of IFNγ on endothelial cells (ECs) and possible molecular mechanisms in angiostasis. By employing Tie2(IFNγR) mice, in which IFNγR expression was reconstituted under the control of Tie2 promoter in IFNγR-deficient mice, we found that the response of ECs to IFNγ was highly effective in inhibiting blood supply and retarding tumour growth. Interestingly, the expression of IFNγR on Tie2(-) cells did not inhibit, but promoted tumour growth in control wild-type mice. Mechanism studies showed that IFNγ reacting on ECs down-regulated the delta-like ligand 4 (Dll4)/Notch signalling pathway. Accordingly, overexpression of Dll4 in human ECs diminished the effect of IFNγ on ECs. This study demonstrates that the action of IFNγ on ECs, but not other cells, is highly effective for tumour angiostasis, which involves down-regulating Dll4. It provides insights for EC-targeted angiostatic therapy in treating angiogenesis-associated disorders in the clinic.

Interferon-γ Safeguards Blood-Brain Barrier during Experimental Autoimmune Encephalomyelitis

“…Tie2-IFNgR mice have been described in our previous study. 22 The genome of Tie2-IFNgR mice is composed of a transgene containing IFNgR cDNA under the control of Tie2 promoter with an endogenous IFNgR-deficient genomic background. Three lines of Tie2-IFNgR mice (W16, W25, and W41) were established.…”

“…22 In brain, the IFNgR was expressed on ECs, and it was also functional in these mice Q19 (Supplemental Figure S1). A minimal expression of IFNgR mRNA could be detected in Tie2 þ bone marrowederived cells in Tie2-IFNgR mice; however, the expression of IFNgR protein on the surface of hematopoietic cells is hardly detectable.…”

“…22,24 Briefly, freshly prepared bone marrow cells of 6-to 8-week-old female IFNgR À/À or Tie2-IFNgR mice were i.v.…”

“…Successful reconstitution of the hematopoietic system was also determined by PCR analysis of IFNgR gene in peripheral blood mononuclear cells 8 weeks after transplantation. 22 Eight weeks after bone marrow transplantation, mice were immunized to induce active EAE, as described above. To evaluate the degree of chimerism, eGFP / IFNgR À/À bone marrow transplantation was included and the mice were examined at 8 weeks after transplantation.…”

Angiogenesis in refractory depression: A possible phenotypic target to avoid the blood brain barrier

“…In these patients having depressive symptoms, serum interleukin (IL)-18 on day 7 was independently associated with incident post-stroke depression (27). IL-18 has been known to suppress angiogenesis (28), probably via interferon-γ (29). There is also a report on tumor necrosis factor (TNF)-alpha, showing a significant inverse correlation between TNF-alpha and EPC levels (21).…”