PlGF, a member of the VEGF family, has proven to be associated with pathological angiogenesis in ocular diseases such as nAMD and proliferative diabetic retinopathy.
35,36 Although its expression is low but constitutive under physiological conditions, PlGF is expressed in various tissues including the heart, lung, and adipose tissue. Previous studies revealed that PlGF was produced by RPE cells under pathological conditions,
25,29 and that PlGF protein levels increased in the aqueous humor of nAMD patients.
37 Increased PlGF selectively binds to VEGFR1, which evokes various transcriptional factors such as AP-1 via the phosphorylation of intracellular signaling molecules (e.g., PI3K/AKT, p38 MAPK, ERK1/2), leading to cell survival and migration.
38–40 AP-1 subunit proteins including ATF, c-Fos, and c-Jun form homo/heterodimers and function as transcriptional factors via binding to the specific promoter and/or enhancer regions of target genes,
41 thus playing important roles in the physiological and pathological processes.
42,43 In the current study, we revealed that PlGF-induced galectin-1
/LGALS1 expression in RPE cells was caused by PI3K/AKT- and p38 MAPK-mediated phosphorylation of AP-1 components ATF2 and c-Jun. We recently demonstrated that IL-1β promoted galectin-1/
LGALS1 expression through the phosphorylation of PI3K/AKT and ERK1/2, followed by AP-1 binding to the AP-1 site in the
LGALS1 enhancer region in Müller glial cells.
14 Interestingly,
LGALS1 expression was not altered by IL-1β application to RPE cells (
Supplementary Fig. S1B) or PlGF application to Müller glial cells (
Supplementary Fig. S1C), underlining the specific cytokine-cell combinations (IL-1β to Müller cells and PlGF to RPE cells) for galectin-1 induction via AP-1 signaling.