Abstract
Besides their long-known critical role in embryonic growth and in cancer development and progression, erythropoietin-producing hepatocellular carcinoma type B (EphB) receptor tyrosine kinases and their ephrin-B ligands are involved in the modulation of immune responses and in remodeling and maintaining the integrity of the intestinal epithelial layer. These processes are critically involved in the pathogenesis of inflammatory-based disorders of the gut, like inflammatory bowel diseases (IBDs). Accordingly, our aim was to investigate the role of the EphB/ephrin-B system in intestinal inflammation by assessing the local and systemic effects produced by its pharmacological manipulation in 2,4,6-trinitrobenzenesulfonic acid (TNBS)- (Th1-dependent model) and dextran sulphate sodium (DSS)- (innate response model) induced colitis in mice. To this purpose, we administered chimeric Fc-conjugated proteins, allegedly able to uni-directionally activate either forward (ephrin-B1-Fc) or reverse (EphB1-Fc) signaling, and the soluble monomeric EphB4 extracellular domain protein, that, simultaneously interfering with both signaling pathways, acts as EphB/ephrin-B antagonist.The blockade of the EphB/ephrin-B forward signaling by EphB4 and EphB1-Fc was ineffective against DSS-induced colitis while it evoked remarkable beneficial effects against TNBS colitis: it counteracted all the evaluated inflammatory responses and the changes elicited on splenic T lymphocytes subpopulations, without preventing the appearance of a splice variant of ephrin-B2 gene elicited by the haptenating agent in the colon. Interestingly, EphB4, preferentially displacing EphB4/ephrin-B2 interaction over EphB1/ephrin-B1 binding, was able to promote Tumor Necrosis Factor alpha (TNFα) release by splenic mononuclear cells in vitro. On the whole, the collected results point to a potential role of the EphB/ephrin-B system as a pharmacological target in intestinal inflammatory disorders and suggest that the therapeutic efficacy of its blockade seemingly works through the modulation of immune responses, independent of the changes at the transcriptional and translational level of EphB4 and ephrin-B2 genes.
Highlights
Eph receptors belong to the largest family of tyrosine kinases receptors (RTKs), divided in A (EphA1-8, 10) and B classes (EphB1-4, 6), according to structural features and binding affinities for their ligands, cell surface-bound ephrins (Eph receptors interacting proteins) (Pasquale, 2005)
The multiplicity of cell targets, involved in inflammatory responses, affected by erythropoietin-producing hepatocellular carcinoma type B (EphB)/ephrin-B signaling pathways (Kania and Klein, 2016) and the documented up-regulation of ephrin-B2 messenger RNA (mRNA) levels in gut mucosal lesions of Crohn’s disease (CD) patients (Hafner et al, 2005) prompted us to focus our attention on the possible involvement of EphB/ephrin-B system in intestinal inflammatory disorders
To this end we applied two murine models of inflammatory bowel diseases (IBDs) characterized by complementary pathogenetic mechanisms: the trinitrobenzenesulfonic acid (TNBS) model, primarily driven by Th1-mediated immune responses, and the dextran sulphate sodium (DSS) one, mainly triggered by innate immunity responses and useful to highlight the efficacy of agents able to re-establish the integrity of the epithelium after injury (Kiesler et al, 2015)
Summary
Eph receptors (erythropoietin-producing hepatocellular carcinoma) belong to the largest family of tyrosine kinases receptors (RTKs), divided in A (EphA1-8, 10) and B classes (EphB1-4, 6), according to structural features and binding affinities for their ligands, cell surface-bound ephrins (Eph receptors interacting proteins) (Pasquale, 2005). Besides its long known critical role in embryonic growth and in cancer development and progression, recent findings have highlighted its involvement in cell adhesion-based responses, in the modulation of immune responses, and in remodeling and maintaining the integrity of the epithelial layer (Funk and Orr, 2013; Perez White and Getsios, 2014). The interaction between EphB4 on leukocytes and endothelial ephrin-B2 regulates endothelial activation, leukocytes adhesion, and transmigration (Pfaff et al, 2008); ephrin-B1, ephrin-B2, and EphB4 are involved in T-cell development and activation (Kawano et al, 2012; Jin et al, 2014), in the organization of stem cell compartments and in the ordered migration of epithelial cells along the intestinal villus axis (Perez White and Getsios, 2014). The EphB/ephrin-B system appears to affect several cellular targets critically involved in the pathogenesis of inflammatory-based disorders, like inflammatory bowel diseases (IBDs)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
