Simplexide Induces CD1d-Dependent Cytokine and Chemokine Production from Human Monocytes

Abstract

Monocytes are major effector cells of innate immunity and recognize several endogenous and exogenous molecules due to the expression of wide spectrum of receptors. Among them, the MHC class I-like molecule CD1d interacts with glycolipids and presents them to iNKT cells, mediating their activation. Simplexide belongs to a novel class of glycolipids isolated from marine sponges and is structurally distinct from other immunologically active glycolipids. In this study we have examined the effects of simplexide on cytokine and chemokine release from human monocytes. Simplexide induces a concentration- and time-dependent release of IL-6, CXCL8, TNF-α and IL-10 and increases the expression of IL6, CXCL8 and IL10 mRNA. Cytokine and chemokine release induced by simplexide from monocytes is dependent on CD1d since: i) a CD1d antagonist, 1,2-bis (diphenylphosphino) ethane [DPPE]- polyethylene glycolmonomethylether [PEG], specifically blocks simplexide-induced activation of monocytes; ii) CD1d knockdown inhibits monocyte activation by simplexide and iii) simplexide induces cytokine production from CD1d-transfected but not parental C1R cell line Finally, we have shown that simplexide also induces iNKT cell expansion in vitro. Our results demonstrate that simplexide, apart from activating iNKT cells, induces the production of cytokines and chemokines from human monocytes by direct interaction with CD1d.

Immunomodulatory properties of characellide A on human peripheral blood mononuclear cells

“…1 A–C). To exclude that the effect of characellide could be due to LPS contamination, a well-characterized stimulus for these cells (Loffredo et al 2014 ), PBMC were stimulated with characellide in the presence of polymyxin B (50 mg/ml), a potent inactivator of LPS (Kolomaznik et al 2018 ). Polymyxin B did not influence the capacity of characellide A to induce the release of CXCL8, IL-6, and TNF-α, whereas it almost completely suppressed the production of cytokines and chemokines induced by LPS (Table 1 ).…”

“…Data are representative of five independent experiments obtained from different donors. *p < 0.05, **p < 0.01, ***p < 0.001 (Loffredo et al 2014). We hypothesized that characellide A could be involved in PBMC activation through the CD1d pathway.…”

“…CD1d binds and presents lipid antigens to natural killer T cells with an invariant T cell receptor alpha chain (iNKT) inducing their development and activation in several pathological conditions such as infection (Skold and Behar 2003 ), autoimmune disorders (Mars et al 2008 ), allergic responses (Lexmond et al 2014 ) and tumor immunity (Ni et al 2015 ). It has been demonstrated that CD1d binds α-galactosylceramide (α-GalCer) and simplexide, two glycolipids isolated from the marine sponges Agelas mauritiana and Plakortis simplex respectively (Koch et al 2005 ; Loffredo et al 2014 ). It was discovered that α-GalCer induced Th1 (IFN-γ) and Th2 (IL-4) cytokine production from human NKT cells in a CD1d-dependent manner (Kawano et al 1997 ; Kronenberg 2005 ).…”

“…It was discovered that α-GalCer induced Th1 (IFN-γ) and Th2 (IL-4) cytokine production from human NKT cells in a CD1d-dependent manner (Kawano et al 1997 ; Kronenberg 2005 ). Simplexide activated human monocytes through CD1d-producing cytokines and chemokines and showed a proinflammatory profile (Loffredo et al 2014 ). Two metabolites belonging to a new class of glycolipopeptides, namely characellide A and B, were recently isolated from the deep sea marine sponge Characella pachastrelloides .…”

Chemistry and Biology of Bioactive Glycolipids of Marine Origin

“…Despite the remarkable structural differences with the plakosides, the simplexides share a very similar biological profile, showing potent inhibitory activity of the proliferarion of T cells in the murine immune system when stimulated with concanavalin A through a noncytotoxic mechanism. Further biological studies demonstrated that the immunosuppressive effects of the simplexides are due to the induction that they exert on the expression and release of cytokines and chemokines from human monocytes by direct interaction with the CD1d receptors, expressed in these cells [ 138 ]. In addition, the simplexides induce the expansion of i NKT (natural killer T cells with an invariant T cell receptor alpha chain).…”