Cutting Edge: Inhibition of IL-6 <i>Trans</i>-Signaling Protects from Malaria-Induced Lethality in Mice

Wunderlich, Claudia M.; Delić, Denis; Behnke, Kristina; Meryk, Andreas; Ströhle, Peter; Chaurasia, Bhagirath; Al‐Quraishy, Saleh; Wunderlich, Frank

doi:10.4049/jimmunol.1102137

Cited by 39 publications

(33 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, when bound to the soluble receptor created, for example, by ectodomain shedding from the membranebound receptor, IL-6 is then also able to communicate, by trans-signaling, with all other cells through the ubiquitously expressed signal transducer GP130. There is evidence that inhibition of IL-6 trans-signaling protects from P. chabaudi malaria (Wunderlich et al 2012). …”

Section: Discussionmentioning

confidence: 99%

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

et al. 2017

Self Cite

View full text Add to dashboard Cite

Epigenetic mechanisms such as DNA methylation are increasingly recognized to be critical for vaccination efficacy and outcome of different infectious diseases, but corresponding information is scarcely available for host defense against malaria. In the experimental blood-stage malaria Plasmodium chabaudi, we investigate the possible effects of a blood-stage vaccine on DNA methylation of gene promoters in the liver, known as effector against blood-stage malaria, using DNA methylation microarrays. Naturally susceptible Balb/c mice acquire, by protective vaccination, the potency to survive P. chabaudi malaria and, concomitantly, modifications of constitutive DNA methylation of promoters of numerous genes in the liver; specifically, promoters of 256 genes are hyper(=up)- and 345 genes are hypo(=down)-methylated (p < 0.05). Protective vaccination also leads to changes in promoter DNA methylation upon challenge with P. chabaudi at peak parasitemia on day 8 post infection (p.i.), when 571 and 1013 gene promoters are up- and down-methylated, respectively, in relation to constitutive DNA methylation (p < 0.05). Gene set enrichment analyses reveal that both vaccination and P. chabaudi infections mainly modify promoters of those genes which are most statistically enriched with functions relating to regulation of transcription. Genes with down-methylated promoters encompass those encoding CX3CL1, GP130, and GATA2, known to be involved in monocyte recruitment, IL-6 trans-signaling, and onset of erythropoiesis, respectively. Our data suggest that vaccination may epigenetically improve parts of several effector functions of the liver against blood-stage malaria, as, e.g., recruitment of monocyte/macrophage to the liver accelerated liver regeneration and extramedullary hepatic erythropoiesis, thus leading to self-healing of otherwise lethal P. chabaudi blood-stage malaria.

show abstract

Section: Discussionmentioning

confidence: 99%

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…In a mouse model of atherosclerosis, sgp130Fc did not only reduce disease, but led to a significant regression of advanced atherosclerosis, most probably through reduced monocyte recruitment and the progression of atherosclerotic plaques [16]. Inhibition of IL-6 trans-signaling was further shown to be protective in an otherwise lethal infection with Plasmodium chabaudi, which causes malaria [17]. The damaging effects of IL-6 in the central nervous system also appear to depend solely upon trans-signaling, as mice which express sgp130 under the GFAP promoter are fully protected [18 ].…”

Section: Il-6 Classic Versus Trans-signalingmentioning

confidence: 97%

The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition

Garbers

Aparicio-Siegmund

Rose-John

2015

Current Opinion in Immunology

355

273

View full text Add to dashboard Cite

“…and the second wave peaking at maximal parasitemia on day 8 p.i. (Wunderlich et al, 2012). In parallel, the liver biphasically produces mRNAs coding for IL-1β, TNFα, and IL-6 (Krücken et al, 2009).…”

Section: Liver Effectors Toward Blood-stage Malariamentioning

confidence: 99%

“…Conversely, decreasing IL-6 levels are reported to be associated with decreasing parasitemia (Sarthou et al, 1997) and hyperpyrexia (Seoh et al, 2003), as well as after anti-malarial treatment (Hugosson et al, 2006). In experimental murine malaria, it has been shown that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality (Wunderlich et al, 2012). Indeed, approximately 50% of IL-6Rα-deficient mice survive an otherwise lethal P. chabaudi blood-stage malaria.…”

Section: Liver Effectors Toward Blood-stage Malariamentioning

confidence: 99%

See 1 more Smart Citation

Liver-inherent immune system: its role in blood-stage malaria

2014

Self Cite

View full text Add to dashboard Cite

The liver is well known as that organ which is obligately required for the intrahepatocyte development of the pre-erythrocytic stages of the malaria-causative agent Plasmodium. However, largely neglected is the fact that the liver is also a central player of the host defense against the morbidity- and mortality-causing blood stages of the malaria parasites. Indeed, the liver is equipped with a unique immune system that acts locally, however, with systemic impact. Its main “antipodal” functions are to recognize and to generate effective immunoreactivity against pathogens on the one hand, and to generate tolerance to avoid immunoreactivity with “self” and harmless substances as dietary compounds on the other hand. This review provides an introductory survey of the liver-inherent immune system: its pathogen recognition receptors including Toll-like receptors (TLRs) and its major cell constituents with their different facilities to fight and eliminate pathogens. Then, evidence is presented that the liver is also an essential organ to overcome blood-stage malaria. Finally, we discuss effector responses of the liver-inherent immune system directed against blood-stage malaria: activation of TLRs, acute phase response, phagocytic activity, cytokine-mediated pro- and anti-inflammatory responses, generation of “protective” autoimmunity by extrathymic T cells and B-1 cells, and T cell-mediated repair of liver injuries mainly produced by malaria-induced overreactions of the liver-inherent immune system.

show abstract

Cutting Edge: Inhibition of IL-6 Trans-Signaling Protects from Malaria-Induced Lethality in Mice

Cited by 39 publications

References 25 publications

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice

The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition

Liver-inherent immune system: its role in blood-stage malaria

Contact Info

Product

Resources

About