Interleukin-4 activates divergent cell-intrinsic signals to regulate retinal cell proliferation induced by classical growth factors

• Published in: Molecular and cellular neuroscience Vol. 123; p. 103780
• Main Authors: da Silva, Gustavo Mataruna, de Figueiredo, Camila Saggioro, da Rocha Oliveira, Amanda Cândida, Raony, Ícaro, de Araújo Miranda, Raphael Amorim, de Mello Silva, Eliezer, Guilarducci, Carla Valéria Vieira, dos Santos, Aline Araujo, Giestal-de-Araujo, Elizabeth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2022
• Subjects: Animals; Cell Proliferation; Cyclin D1 - metabolism; Development; Epidermal growth factor; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; Fibroblast growth factor; Fibroblast Growth Factor 2 - pharmacology; Interleukin-4; Interleukin-4 - metabolism; Interleukin-4 - pharmacology; Rats; Retina; Retina - metabolism; Tumor Suppressor Protein p53; Cell proliferation; Development; Fibroblast growth factor; Interleukin-4; Retina; Epidermal growth factor
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2022.103780

In the developing retina, precise coordination of cell proliferation, differentiation, and survival is essential for proper retinal maturation and function. We have previously reported evidence that interleukin-4 (IL-4) plays critical roles in neuronal differentiation and survival during retinal development. However, little is known about the role of IL-4 on retinal cell proliferation. In the current study, we investigated if IL-4 regulates cell proliferation induced by epidermal growth factor (EGF) and by fibroblast growth factor 2 (FGF2) in primary retinal cell cultures obtained from newborn rats. First, we show that EGF and FGF2 act as mitogens for glial cells, increasing proliferation of these cells in the retina. EGF- and FGF2-induced mitogenesis requires activation of distinct cell-intrinsic signals. In retinal cells exposed to FGF2, IL-4 downregulates p53 levels (a protein whose activation induces cell-cycle arrest) and increases mitogenic responsiveness to FGF2 through activation of protein kinase A (PKA) pathway. Conversely, in retinal cells exposed to EGF, IL-4 downregulates cyclin D1 levels (a protein required for cell-cycle progression), upregulates p53 levels, and decreases mitogenic responsiveness to EGF. The inhibitory effect induced by IL-4 on retinal cells exposed to EGF requires activation of Janus kinase 3 (JAK3), but not activation of PKA. Based on previous and current findings, we propose that IL-4 serves as a node of signal divergence, modulating multiple cell-intrinsic signals (e.g., cyclin D1, p53, JAK3, and PKA) and mitogenic responsiveness to cell-extrinsic signals (e.g., FGF2 and EGF) to control cell proliferation, differentiation, and survival during retinal development. •EGF and FGF2 increase cell proliferation, acting as mitogens for retinal glial cells.•EGF- and FGF2-induced retinal cell proliferation requires distinct cell-intrinsic signals.•IL-4 ensures homeostatic proliferation by controlling mitogenic responsiveness to EGF and FGF2.•IL-4 increases mitogenic responsiveness to FGF2 through PKA activation and p53 downregulation.•IL-4 decreases mitogenic responsiveness to EGF through JAK3 activation, p53 upregulation, and cyclin D1 downregulation.