MASP-1 Induces a Unique Cytokine Pattern in Endothelial Cells: A Novel Link between Complement System and Neutrophil Granulocytes

Péter K Jani,Márton Megyeri,József Dobó,Csaba I Tímár,Zoltán Doleschall,László Cervenak,Péter Gál,Veronika Makó,Krisztina Futosi,Attila Mócsai,Erika Kajdácsi,Ger Van Zandbergen

doi:10.1371/journal.pone.0087104

Abstract

Microbial infection urges prompt intervention by the immune system. The complement cascade and neutrophil granulocytes are the predominant contributors to this immediate anti-microbial action. We have previously shown that mannan-binding lectin-associated serine protease-1 (MASP-1), the most abundant enzyme of the complement lectin pathway, can induce p38-MAPK activation, NFkappaB signaling, and Ca2+-mobilization in endothelial cells. Since neutrophil chemotaxis and transmigration depends on endothelial cell activation, we aimed to explore whether recombinant MASP-1 (rMASP-1) is able to induce cytokine production and subsequent neutrophil chemotaxis in human umbilical vein endothelial cells (HUVEC). We found that HUVECs activated by rMASP-1 secreted IL-6 and IL-8, but not IL-1alpha, IL-1ra, TNFalpha and MCP-1. rMASP-1 induced dose-dependent IL-6 and IL-8 production with different kinetics. rMASP-1 triggered IL-6 and IL-8 production was regulated predominantly by the p38-MAPK pathway. Moreover, the supernatant of rMASP-1-stimulated HUVECs activated the chemotaxis of neutrophil granulocytes as an integrated effect of cytokine production. Our results implicate that besides initializing the complement lectin pathway, MASP-1 may activate neutrophils indirectly, via the endothelial cells, which link these effective antimicrobial host defense mechanisms.

Highlights

The immune system responds to various pathogens through different sets of immune mechanisms
We described that a unique cytokine profile, produced by recombinant MASP-1 (rMASP-1)-stimulated human umbilical vein endothelial cells (HUVEC), is able to induce chemotaxis of neutrophil granulocytes, as a novel link between the complement system and the endothelial cell-mediated regulation of the neutrophil response
Activation of CREB and JNK by rMASP-1 Previously, we reported that rMASP-1 could activate p38

Summary

Introduction

The immune system responds to various pathogens through different sets of immune mechanisms. The complement system is part of the innate immune system It can recognize, identify, and eliminate invading pathogens and altered host cells. The complement system can be activated through three different routes: the classical, the lectin, and the alternative pathways. We showed that rMASP-1 can cleave PAR-1, 2, and 4 with different efficacy, and PAR-4 activation leads to Ca2+-signaling, the nuclear translocation of NFkappaB, and the phosphorylation of p38-MAPK. Cytokine-generation during the inflammatory response requires the involvement of the p38-MAPK, JNK, NFkappaB or cAMP responding elementbinding protein (CREB) signaling pathways [8,9,10,11,12]

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