Growth Differentiation Factor-15–Induced Contractile Activity and Extracellular Matrix Production in Human Trabecular Meshwork Cells

Abstract

PurposeTo determine the role and regulation of growth differentiation factor-15 (GDF-15), a TGF-β–related cytokine in human trabecular meshwork (TM) cells in the context of aqueous humor (AH) outflow and IOP.MethodsRegulation of expression by external cues, and the distribution and secretion of GDF-15 by human TM primary cell cultures, and the effects of recombinant (r) GDF-15 on TM cell contractile characteristics, actin cytoskeleton, cell adhesion, extracellular matrix (ECM), α-smooth muscle actin (αSMA), SMAD signaling, and gene expression were determined by immunoblot, immunofluorescence, mass spectrometry, cDNA microarray, and real-time quantitative PCR (RT-qPCR) analyses.ResultsGrowth differentiation factor-15, a common constituent of ECM derived from the human TM cells, was confirmed to be distributed throughout the conventional aqueous humor outflow pathway of the human eye. Growth differentiation factor-15 protein levels were significantly increased in human TM cells in response to TGF-β2, dexamethasone, endothelin-1, lysophosphatidic acid, TNF-α, IL-1β treatment, and by cyclic mechanical stretch. Stimulation of human TM cells with rGDF-15 caused a significant increase in the formation of actin stress fibers and focal adhesions, myosin light chain phosphorylation, SMAD signaling, gene expression, and the levels of αSMA and ECM proteins.ConclusionsThe results of this study, including a robust induction of GDF-15 expression by several external factors known to elevate IOP, and rGDF-15–induced increase in contractility, cell adhesion, and the levels of ECM proteins and αSMA in TM cells, collectively suggest a potential role for GDF-15 in homeostasis and dysregulation of AH outflow and IOP in normal and glaucomatous eyes, respectively.

Predicted protein interactions of IFITMs may shed light on mechanisms of Zika virus-induced microcephaly and host invasion

“…FNDC3B- a novel interactor of IFITM3 promotes cell migration by cooperating with ANXA2 96 . FNDC3B has been found to be upregulated in samples of hepatocellular carcinoma infected with HBV (Hepatitis B virus) or HCV and overexpressed in normal liver tissue infected with viral hepatitis 97 . It has also been reported that the expression of FNDC3B increases on induction of GDF-15 which is known to regulate expression of genes that orchestrate changes in cytoskeleton and adhesion junctions 97 .…”

“…FNDC3B has been found to be upregulated in samples of hepatocellular carcinoma infected with HBV (Hepatitis B virus) or HCV and overexpressed in normal liver tissue infected with viral hepatitis 97 . It has also been reported that the expression of FNDC3B increases on induction of GDF-15 which is known to regulate expression of genes that orchestrate changes in cytoskeleton and adhesion junctions 97 . In this respect, it is interesting to note that IFITM3 has been suggested to inhibit early stages of Zika virus infection by directly altering the properties of cell and/or viral membranes and blocking formation of fusion pores 98 .…”

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

“…Very importantly, several authors have reported that commercially available GDF-15 preparations are often contaminated with variable bioactive levels of TGF-β1 ( (15,26,27) and others [Pierre Coulie, personal communication]). Signal transduction through SMAD2/3 or via TGFβRII interaction may thus be artifacts caused by contaminating TGF-β1 rather than by GDF-15 itself (7,52,144). Therefore, studies reporting TGF-β related effects induced by recombinant human GDF-15 need to be regarded with great caution.…”

The impact of growth differentiation factor 15 on the risk of cardiovascular disease: evidence from Mendelian randomization study

“…Likely, during 1.9 years of follow-up, an annual rate of stroke or systemic embolic events was 2.03% in AF patients with GDF-15 in the highest quartile (>2052 ng/L) while 0.90% in the lowest quartile (≤977 ng/L) in ARISTOTLE trial [45]. Mechanistically, on the one hand, systemic in ammation especially IL-1β, IL-6 and TNF-α was a potential mechanism promoting the formation of cerebral cardioembolism [46] and GDF-15 was proved related to them [47] [48]. On the other hand, AF, HF, CAD were one of the precondition of cardioembolic strokes which were a liated to augment of serum GDF-15 [49].…”