Characterization of Endocannabinoid System and Interleukin Profiles in Ovine AEC: Cannabinoid Receptors Type-1 and Type-2 as Key Effectors of Pro-Inflammatory Response

Abstract

Amniotic epithelial cells (AEC) have been proposed as promising clinical candidates for regenerative medicine therapies due to their immunomodulatory capacity. In this context, the endocannabinoid system (ECS) has been identified as mediating the immune-stem cell dialogue, even if no information on AEC is available to date. Therefore, this study was designed to assess whether ECS is involved in tuning the constitutive and lipopolysaccharide (LPS)-induced ovine AEC anti-inflammatory and pro-inflammatory interleukin (IL-10, IL-4, and IL-12) profiles. Firstly, interleukins and ECS expressions were studied at different stages of gestation. Then, the role of cannabinoid receptors 1 and 2 (CB1 and CB2) on interleukin expression and release was investigated in middle stage AEC using selective agonists and antagonists. AEC displayed a degradative more than a synthetic endocannabinoid metabolism during the early and middle stages of gestation. At the middle stage, cannabinoid receptors mediated the balance between pro-inflammatory (IL-12) and anti-inflammatory (IL-4 and IL-10) interleukins. The activation of both receptors mediated an overall pro-inflammatory shift—CB1 reduced the anti-inflammatory and CB2 increased the pro-inflammatory interleukin release, particularly after LPS stimulation. Altogether, these data pave the way for the comprehension of AEC mechanisms tuning immune-modulation, crucial for the development of new AEC-based therapy protocols.

Amniotic Epithelial Stem Cells Counteract Acidic Degradation By-Products of Electrospun PLGA Scaffold by Improving Their Immunomodulatory Profile In Vitro

“…oAECs are able to secrete cytokines and growth factors with antiapoptotic, proangiogenic, and immune-modulatory molecules, which can alter the pro-inflammatory signals and enhance the anti-inflammatory ones, hence improving tissue regeneration [84][85][86][87][88]. Among them, it was recently demonstrated in the amniotic epithelium that a highly conserved physiological mechanism amongst species controlling the expression and releasing balance of potent anti-inflammatory and proinflammatory cytokines, such as interleukin (IL)-10, IL-4, and IL-12, under both basal and LPS-inductive conditions [54,80,89,90].…”

The Impact of CB1 Receptor on Inflammation in Skeletal Muscle Cells

“…16 Interleukin-6 (IL-6) is an inflammatory cytokine and mediator that affects immune and nonimmuno-regulation in a variety of cell types and tissues outside of the immune system, including skeletal muscle tissue. 12,[17][18][19] IL-6 is a physiologically active cytokine that regulates inflammatory responses, skeletal muscle cell proliferation, differentiation, growth, and metabolism. 20 Recent data has shown that IL-6 is generated and released from skeletal muscle cells in the absence of inflammation and by complex signalling cascades.…”

“…14,15 Previous studies have demonstrated that skeletal muscle tissue produces IL-6. 12,19 Increasing evidence indicates that skeletal muscle is implicated in the inflammatory process via secreting cytokines. 23 The effects of cannabinoids on muscle cell cytokine expression have not been evaluated.…”

Unveiling the immunomodulatory shift: Epithelial-mesenchymal transition Alters immune mechanisms of amniotic epithelial cells

“… 35 , 36 To this regard, here we demonstrate that the transient depletion of CIITA dramatically impairs the anti-inflammatory abilities of eAEC, thus demonstrating its pivotal role in the immune response of these cells. 37 …”