Interferon-Beta Increases Plasma Ceramides of Specific Chain Length in Multiple Sclerosis Patients, Unlike Fingolimod or Natalizumab

Abstract

Fingolimod is used for the treatment of multiple sclerosis (MS) and targets receptors for the bioactive sphingolipid sphingosine-1-phosphate (S1P). Whether fingolimod or other MS therapies conversely affect plasma concentrations of sphingolipids has, however, not yet been analyzed. Herein, we quantified 15 representative sphingolipid species by mass spectrometry in plasma from relapsing-remitting MS patients currently under fingolimod (n = 24), natalizumab (n = 16), or IFN-β (n = 18) treatment. Healthy controls (n = 21) and untreated MS patients (n = 11) served as control groups. IFN-ß treatment strongly increased plasma level of C16:0, C18:0, C20:0, and C24:1 ceramides compared to healthy controls, untreated patients, or patients receiving fingolimod or natalizumab medication. Natalizumab treatment increased plasma concentrations of both S1P and sphinganine-1-phosphate, whereas fingolimod treatment did not affect any of these lipids. Correlations of sphingolipids with the Expanded Disability Status Scale and other disease specific parameters revealed no systemic change of sphingolipids in MS, independent of the respective treatment regime. These results indicate type I interferon treatment to cause a strong and specific increase in ceramide level. If confirmed in larger cohorts, these data have implications for the efficacy and adverse effects of IFN-β. Moreover, quantification of ceramides soon after therapy initiation may help to identify therapy-responsive patients.

Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course

“…To further validate these results, we conducted a similar experiment but exposed the cells to the cocktail of ceramide species which we identified as differentially abundant in the normal and high BMI groups of MS patients (Ceramide C16:0, C22:0, and C24:1). Each cocktail was prepared based on the physiological ceramide concentrations detected in human plasma [37,71,72] and reflected the relative high or low abundance of ceramide species detected in our lipidomic analysis. Monocytes exposed for 24 h to the cocktail corresponding to the ceramide species levels detected in the plasma samples from MS patients with high BMI showed increased proliferation and DNA methylation compared to cells exposed to the lower concentrations of ceramides, equivalent to those detected in the normal BMI MS group (Fig.…”

The Evaluation of Oxidative Stress Parameters in Serum Patients with Relapsing‐Remitting Multiple Sclerosis Treated with II‐Line Immunomodulatory Therapy

“…That study did not consider the type of treatment. Other studies conducted on patients with II-line therapy (FG, NT) did not show an increase in OS parameters such as ceramides and the EDSS scale [ 69 ]. The short-chain ceramides stimulated oxygen species production and led to neuronal death [ 70 , 71 ].…”

Targeting Sphingosine Kinases for the Treatment of Cancer

“…In particular, we hypothesize that inhibition of SK activity will alter signaling through the PD-1/PD-L1 pathway such that the host immune response to the cancer is improved. This postulate is based on the observations that PD-L1 expression in tumor cells is induced by IFN-γ (Cheng et al, 2007; Dondero et al, 2016; Iwai et al, 2002; Muhlbauer et al, 2006), and IFN-γ signaling is dependent on sphingolipid metabolism (Bajwa et al, 2017; Ottenlinger et al, 2016; Seo, Alexander, & Hahm, 2011; Wakita, Nishimura, Tokura, Furukawa, & Takigawa, 1996). Furthermore, Akt- (Abdelhamed, Ogura, Yokoyama, Saiki, & Hayakawa, 2016; Atefi et al, 2014; Dong et al, 2016; Lastwika et al, 2016; Song et al, 2013; Yang et al, 2017; Zhao et al, 2017), NF-kB- (Gowrishankar et al, 2015), and TNFα- (Wang et al, 2017) signaling induce PD-L1 expression, and all of these pathways are regulated by sphingolipid signaling.…”