Mannose binding lectin enhances IL-1β and IL-10 induction by non-lipopolysaccharide (LPS) components of Neisseria meningitidis
Introduction
Meningococcal disease, caused by the Gram-negative diplococcus Neisseria meningitidis, is an important cause of mortality and morbidity, particularly in children. The clinical course of the disease ranges from meningitis with a relatively benign clinical picture and a mortality rate of less then 5% to fulminant meningococcal sepsis with a rapidly deteriorating clinical condition and a mortality rate ranging from 20 to 50% [1].
Disease severity and mortality in meningococcal disease are correlated with high plasma concentrations of the pro-inflammatory cytokines TNFα and IL-1β, which induce shock and disseminated intravascular coagulation [2], [3]. However, cytokines play a complex dual role in the pathophysiology of invasive meningococcal disease, as it also has been shown that a low production capacity for TNFα combined with a high production capacity for the anti-inflammatory cytokine IL-10 or poor regulation of the IL-1 system constitute a risk factor for invasive disease [4], [5]. Meningococcal lipopolysaccharide (LPS) is generally considered to be the main cytokine-inducing element [6]. Using LPS-deficient mutant N. meningitidis we and others have shown however, that non-LPS components of the meningococcus can also induce cytokine production in human monocytes or macrophages [7], [8], [9].
Mannose binding lectin (MBL) is a pattern-recognition molecule present in serum that is involved in the innate immune defence by activation of complement, promotion of opsonophagocytosis and modulation of inflammatory mediators [10]. Serum concentrations of MBL are determined by structural mutations in the exon 1 region and polymorphism of the promoter region of the MBL-gene (Caucasian median value: 1600 ng/mL) [11], [12]. Homozygousity for any of the 3 structural mutations in the exon 1 region reduces serum levels of MBL to values <100 ng/mL, whereas heterozygousity for these mutations also profoundly reduces MBL concentrations to levels <400 ng/mL. The presence of promoter polymorphisms contributes to the wide range of MBL concentrations as observed in the general population. In addition, MBL is an acute phase protein and during inflammation levels can increase some three-fold [13]. Recent evidence suggests that MBL plays a role in the pathogenesis of meningococcal disease. MBL can bind meningococci, activate complement and increase killing of these organisms [14], [15]. In addition, genetic deficiency for MBL has been shown to increase susceptibility to meningococcal infection, particularly in children [16], [17], [18]. However, the exact pathophysiological role of MBL in meningococcal disease is incompletely understood.
MBL has been reported to influence also the cytokine network after stimulation with various microorganisms [19], [20], [21]. Knowing the crucial role of the cytokine network in meningococcal disease, the principal aim of the present study was to assess the role of MBL in cytokine induction by LPS and by non-LPS components of N. meningitidis.
Section snippets
Meningococcal strains, lipopolysaccharide and mannose binding lectin
The wild-type encapsulated serogroup B N. meningitidis H44/76 strain (indicated as LPS+N. meningitidis) was isolated from a patient with invasive meningococcal disease [22]. The meningococcal strain H44/76lpxA (indicated as LPS−N. meningitidis) is a viable isogenic mutant completely devoid of LPS in the outer membrane. Absence of LPS in this strain was confirmed as described previously [23]. Absence of LPS-activity in the lpxA batch-suspension was confirmed by non-reactivity in the Limulus
MBL-binding LPS+ and LPS− meningococci
Dot blotting experiments (Fig. 1) showed that both LPS+ (B) and LPS− (D) meningococci were able to bind MBL. Binding of these two strains was at a lower level than to the B1940cpsD− mutant (C), but substantially more than to the B1940 strain (A).
Cytokine induction by MBL
Purified MBL did not induce IL-1 and TNFα production in concentrations of MBL ranging from 0.75 to 2500 ng/mL. IL-10, IFNγ and IL-6 inductions by purified MBL were tested at a single concentration (2500 ng/mL), but again we observed no effect on the
Discussion
The principal findings of the present study are that MBL augmented IL-1β and IL-10 production by human PBMCs induced by non-LPS components of meningococci. In contrast, TNFα, IL-6 and IFNγ production was unaffected, suggesting a differential role of MBL in the signalling pathways for IL-1β and IL-10 on one hand, and TNFα, IL-6 and IFNγ on the other. In addition, we found that the LPS+ as well as the LPS− meningococci were able to bind MBL to a similar extent.
MBL reportedly binds to repeating
Acknowledgements
The authors thank Trees Verver for assistance with the stimulation experiments and cytokine assays and Marina Johnson for assistance in determining MBL-binding to the bacteria. Financial support was obtained by a grant from the ‘Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)’ grant number 920-03-176 and from the VSB foundation contract no. CN-6444. This research was also supported by grant support from the Wellcome trust, project grant no. 059247, and Action Research, project
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2014, Clinical Microbiology and InfectionCitation Excerpt :This implies a subtle contribution by MBL2 to innate immunity, that is insufficient to render individuals grossly susceptible to invasive disease. Previous in vitro data suggests that MBL phenotype together with circulating levels of IL1β and IL10 may have a combinatorial effect on the pro-inflammatory cytokine cascade [12], and that MBL2 promotes non-opsonic phagocytosis of N. meningitidis by human macrophages [13]. Thus, in individuals homozygous for the defective MBL2 alleles, a reduced level of MBL2 and associated reduction in the levels of inflammation may give rise to a higher detected peripheral bacterial load.
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Dissecting the pathophysiologic role of endogenous lectins: Glycan-binding proteins with cytokine-like activity?
2007, Cytokine and Growth Factor Reviews