The Aryl Hydrocarbon Receptor–Dependent TGF-α/VEGF-B Ratio Correlates With Disease Subtype and Prognosis in Multiple Sclerosis

TGF-α (A) and VEGF-B (B) levels as well as AHR agonistic activity (D) were assessed in serum samples of patients with RRMS in remission (n = 98), RRMS during relapse (n = 54), and controls (n = 44). TGF-α and VEGF-B levels were measured in pg/mL using a human TGF-α or VEGF-B ELISA. TGF-α/VEGF-B ratio (C) was determined by dividing TGF-α levels by VEGF-B levels. An AHR ligand–sensitive luciferase assay was used. Relative activity was calculated by dividing firefly luciferase activity (pGud-Luc) by Renilla luciferase activity (pTK-Renilla). Values are means of duplicate measurements. Lines represent median and interquartile range. Significance levels were derived using the nonparametric Kruskal-Wallis test with the Dunn multiple comparison test correcting for multiple comparisons. ****p < 0.0001, ***p < 0.001, **p < 0.001, *p < 0.01, and ns = nonsignificant. AHR = aryl hydrocarbon receptor; RRMS = relapsing-remitting multiple sclerosis; TGF-α = transforming growth factor alpha; VEGF-B = vascular endothelial growth factor B.

TGF-α (A) and VEGF-B (B) levels as well as AHR agonistic activity (D) were assessed in serum samples of patients with RRMS in remission (n = 98), CIS (n = 20), and controls (n = 44). TGF-α and VEGF-B levels were measured in pg/mL using a human TGF-α or VEGF-B ELISA. TGF-α/VEGF-B ratio (C) was determined by dividing TGF-α levels by VEGF-B levels. An AHR ligand–sensitive luciferase assay was used. Relative activity was calculated by dividing firefly luciferase activity (pGud-Luc) by Renilla luciferase activity (pTK-Renilla). Values are means of duplicate measurements. Lines represent median and interquartile range. Significance levels were derived using the nonparametric Kruskal-Wallis test with the Dunn multiple comparison test correcting for multiple comparisons. ****p < 0.0001, ***p < 0.001, **p < 0.001, *p < 0.01, and ns = nonsignificant. AHR = aryl hydrocarbon receptor; CIS = clinically isolated syndrome; RRMS = relapsing-remitting multiple sclerosis; TGF-α = transforming growth factor alpha; VEGF-B = vascular endothelial growth factor B.

TGF-α/VEGF-B ratio (A) and AHR agonistic activity (B) in serum samples of patients with RRMS in remission (n = 98) were assessed. TGF-α and VEGF-B levels were measured in pg/mL using a human TGF-α or VEGF-B ELISA. TGF-α/VEGF-B ratio was determined by dividing TGF-α levels by VEGF-B levels. An AHR ligand–sensitive luciferase assay was used. Relative activity was calculated by dividing firefly luciferase activity (pGud-Luc) by Renilla luciferase activity (pTK-Renilla). Values are presented as means of duplicate measurements. Line shows linear regression of the TGF-α/VEGF-B ratio or AHR agonistic activity and patients' EDSS. Significance levels were derived using Spearman correlation analysis (A: Spearman r = −0.2427; R² = 0.059; B: Spearman r = −0.2433; R² = 0.059). AHR = aryl hydrocarbon receptor; EDSS = Expanded Disability Status Scale; RRMS = relapsing-remitting multiple sclerosis; TGF-α = transforming growth factor alpha; VEGF-B = vascular endothelial growth factor B.