Simplexide induces CD1d-dependent cytokine and chemokine production from human monocytes.

Stefania Loffredo,Annunziata Frattini,Alfonso Mangoni,Maria Teresa Lepore,Gianni Marone,Francescopaolo Granata,Francesco Borriello,Valeria Costantino,Rosaria I Staiano,Massimo Triggiani,Paul Proost

doi:10.1371/journal.pone.0111326

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.

Highlights

Monocytes are a critical component of the mononuclear phagocyte system and play an important role in conditions as diverse as infections, cardiovascular diseases and cancer [1,2,3]
Simplexide induces the release of cytokines and chemokines from human monocytes In a first group of experiments we examined the effects of simplexide on cytokine and chemokine production by human monocytes
Polymyxin B did not influence the capacity of simplexide to induce the release of IL-6, CXCL8 and TNF-a, whereas it almost completely suppressed the production of cytokines and chemokines induced by LPS (Table 1)

Summary

Introduction

Monocytes are a critical component of the mononuclear phagocyte system and play an important role in conditions as diverse as infections, cardiovascular diseases and cancer [1,2,3]. By expressing a wide spectrum of surface receptors, monocytes can recognize several chemically unrelated molecules (e.g. proteins and lipids) [4,5,6,7]. Glycolipids and glycosphingolipids are major components of several microorganisms, and are increasingly recognized as potent activators of immune cells [8,9]. These molecules can interact with the MHC class I-like molecule CD1d expressed on antigen presenting cells (APC), such as dendritic cells and monocytes [10,11]. Natural killer T cells with an invariant T cell receptor alpha chain (iNKT) recognize microbial glycolipids bound to and presented by CD1d [12,13,14]. It is well established that presentation of the CD1d-a-

Methods

Results

Conclusion