Up‐regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells

Abstract

Development and homeostasis of multicellular organisms require interactions between neighbouring cells. We recently established an in vitro model of cell-cell interaction based on a collagen vitrigel membrane. We have now examined the role of neural cells in retinal homeostasis by coculture of human retinal pigment epithelial (RPE) cells and neural cells on opposite sides of such a membrane. The neural cells (differentiated PC12 cells) induced up-regulation of semaphorin 4A (Sema4A), a member of the semaphorin family of neural guidance proteins, in RPE (ARPE19) cells. This effect of the neural cells was mimicked by the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and was abolished by the PACAP antagonist PACAP(6-38). Coculture with neural cells or stimulation with PACAP also induced the phosphorylation of extracellular-signal-regulated kinase in ARPE19 cells, and this effect of the neural cells was inhibited by PACAP(6-38). Finally, among various cytokines examined, only the amount of interleukin-6 released by cocultures of ARPE19 and neural cells differed from that released by ARPE19 cells cultured alone. Interleukin-6 was not detected in culture supernatants of neural cells, and the reduction in the amount of interleukin-6 released by the cocultures compared with that released by ARPE19 cells alone was prevented by PACAP(6-38). Our findings suggest that PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function. Development and homeostasis of multicellular organisms require interactions between neighbouring cells. With the use of a coculture system based on a collagen vitrigel membrane, we have now shown that neural cells induce up-regulation of the neural guidance protein Sema4A in RPE cells. This effect of neural cells appears to be mediated by the neuropeptide PACAP. PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may thus regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function.

Protective Effects of PACAP in the Retina

“…Furthermore, PACAP6-38 downregulated the cytokine IL-6 expression, indicating that endogenous PACAP participates in the neural cell-induced IL-6 production (other cytokines out of the tested ones were not infl uenced by the neuronal co-culture). These results suggest that the PACAP secreted by neural cells regulates several factors secreted by RPE cells, important for retinal development and homeostasis [ 54 ]. The local secretion of PACAP necessary for these effects is supported by the high concentration used in this study (1 μM and 10 μM PACAP, lower concentrations were not reported), a concentration much higher than the ones reported to exert protective effects against oxidative stress [ 52 , 53 ].…”

“…A more recent study has reported that PACAP regulates semaphorin4A expression from RPE cells [ 54 ]. The semaphorin protein family has members that infl uence brain and retinal development, by providing neural guidance.…”

Berberine ameliorates collagen‐induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut

“…More recently, peripheral neurons and gastrointestinal tract, in particular δ cells, are also recognized to express CST . Here, we evaluated the effect of berberine on the generation of CST in nerve growth factor‐induced PC12 cells (neural cell line) and STC‐1 cells (gastrointestinal endocrine cell line) . As shown in Fig.…”

PACAP and VIP Inhibit HIF‐1α‐Mediated VEGF Expression in a Model of Diabetic Macular Edema

“…PACAP and VIP play their role not only in the central nervous system, but also in various organs and peripheral tissues where they are largely distributed, and exert cytoprotection (Wei and Mojsov, ; D'Agata and Cavallaro, ; Pilzer and Gozes, ; Castorina et al, ; Giunta et al, ; Elekes et al, ; Reglodi et al, ). It has been previously demonstrated that PACAP and VIP play a protective function in several types of retinal pathology, including DME (Zhang et al, ; Mester et al, ; Fabian et al, ; Giunta et al, ; Szabo et al, ; Szabadfi et al, ; Ko et al, ).…”