HSP70-1 is required for interleukin-5-induced angiogenic responses through eNOS pathway

Abstract

We report a pivotal role for IL-5 as an angiogenic activator. IL-5 increased proliferation, migration and colony tube formation in HUVECs associated with the phosphorylation of ERK and AKT/eNOS, and promoted microvessel sprouting from an angiogenesis animal model. The angiogenic effects were confirmed in IL-5-deficient mice and addition of IL-5 antibody. HSP70-1 was identified via expression profiling following IL-5 stimulation. A siRNA knockdown of HSP70-1 suppressed angiogenic responses and eNOS phosphorylation induced by IL-5. HSP70-1 overexpression enhanced IL-5-induced angiogenic responses. In addition, IL-5-induced neo-vascular formation was verified in both HSP70-1 knockout and HSP70-1 transgenic mice. Furthermore, transcription factor AP-1 was a main factor in IL-5-induced HSP70-1 in response to ERK and AKT signaling pathway. Angiogenic responses induced by VEGF had no effect in either HSP70-1 siRNA in vitro or HSP70-1 knockout mice. IL-5-induced angiogenic responses depended on the binding of IL-5Rα. Our data demonstrate that binding of IL-5 to IL-5Rα receptors enhances angiogenic responses by stimulating the expression of HSP70-1 via the eNOS signaling pathway.

Anti‐interleukin‐5‐neutralizing antibody attenuates caradiac injury and cadiac dysfunction by aggravating the inflammatory response in doxorubicin‐treated mice

“…These data suggest that IL‐5 may be involved in the progression and development of DOX‐induced cardiac injury. Given that T lymphocytes and Mø are the most important sources of IL‐5 (Sewell et al, 1998; Deo et al, 2010; Takatsu, 2011; Park et al, 2017), to determine the effects of DOX on IL‐5 mRNA expression, both T lymphocytes and Mø were collected and treated with either saline or DOX. Interestingly, DOX treatment significantly reduced the mRNA level of IL‐5 in Mø but had no significant effects on lymphocytes.…”

HSP70 Multi-Functionality in Cancer

“…Kim and colleagues showed that extracellular HSP70 can bind to the surface of endothelial cells and induce angiogenesis by ERK-dependent mechanism [180]. In addition, it has been reported that HSP70 enhances IL-5-induced angiogenesis via endothelial nitric oxide synthase (eNOS) pathway, suggesting an inflammatory role of HSP70 in promoting angiogenesis [181].…”

HSP70–eIF4G Interaction Promotes Protein Synthesis and Cell Proliferation in Hepatocellular Carcinoma

“…Furthermore, a promising OS was achieved after membrane HSP70 (mHSP70) positive stage IIIb non-small cell lung carcinoma (NSCLC) patients were treated with combination therapy of radiochemotherapy (RCT), HSP70 peptide, Interleukin-2 (IL-2) activated NK cells, and PD-1 inhibition [62]. New data discussed the role of HSP70-1A as a new type of angiogenesis regulator that enhanced Interleukin-5 (IL-5) induced angiogenesis in vivo and increased the phosphorylation of the extracellular-signal-regulated kinase (ERK) activating ERK-dependent angiogenesis [63,64]. Therefore, the effect of the combination of immune checkpoint inhibitors and angiogenesis inhibitors on the interaction of HSP70 and eIF4G needs to be explored further.…”