IL-4 Induces Cholinergic Differentiation of Retinal Cells In Vitro

Abstract

Interleukin-4 (IL-4) is a pleiotropic cytokine that regulates several phenomena, among them survival and differentiation of neuronal and glial cells. The aim of this work was to investigate the effect of IL-4 on the cholinergic differentiation of neonatal rat retinal cells in vitro, evaluating its effect on the levels of cholinergic markers (CHT1-high-affinity choline transporter; VAChT-vesicular acetylcholine transporter, ChAT-choline acetyltransferase, AChE-acetylcholinesterase), muscarinic receptors, and on the signaling pathways involved. Lister Hooded rat pups were used in postnatal days 0-2 (P0-P2). Our results show that IL-4 treatment (50 U/mL) for 48 h increases the levels of the cholinergic transporters VAChT and CHT1, the acetylcholinesterase activity, and the number of ChAT-positive cells. It also induces changes in muscarinic receptor levels, leading to a small decrease in M1 levels and a significant increase in M3 and M5 levels after 48 h of treatment. We also showed that IL-4 effect on M3 receptors is dependent on type I IL-4 receptor and on an increase in NFκB phosphorylation. These results indicate that IL-4 stimulates cholinergic differentiation of retinal cells.

Interleukin 4 Leads to Sustained Phosphorylation of the STAT6 and ERK Pathways in the Retina and Disrupts Subcortical Visual Circuitry in Rodents

“…During this period (PND10 to PND14), retinal activity that instructs the formation of retinotectal map is driven by cholinergic, and then glutamatergic activity [16]. In the retina, IL-4 exerts a modulatory effect on the cholinergic system [32] and an imbalance in cholinergic activity disrupts the retinotectal topography [14,16]. Therefore, it is possible to postulate that IL-4 modulates this activity, and, as a consequence, the distribution of retinal axons in the SC.…”

Role of Choline in Ocular Diseases

“…Distinct distributions of choline acetyltransferase (+) vs. AchE (+) cells in the inner half of the retina provide graded distributions of ACh, which can direct cell differentiation and network formation [ 74 ]. The cholinergic differentiation of neonatal rat retinal cells in vitro is stimulated by IL-4 [ 75 ]. Acetylcholine-related molecules in the retina are implicated in the communication between photoreceptors and the retinal pigment epithelium [ 76 ].…”