Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration

Drucker, Claudia; Gewiese, Jessica; Malchow, Sven; Scheller, Jürgen; Rose-John, Stefan

doi:10.1016/j.jaut.2009.08.003

Cited by 74 publications

(53 citation statements)

References 98 publications

(130 reference statements)

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“…Nevertheless, IL-6 is also able to engage an alternative pathway through the nat-urally occurring soluble IL-6Ra (sIL-6Ra), which is derived by shedding of the ectodomain of membrane IL-6Ra and by alternative mRNA splicing. The IL-6/sIL-6Ra complex can communicate with all cells by binding to the ubiquitously expressed membrane GP130, thus initiating the so-called "IL-6 trans-signaling process" (13,14). sIL-6Ra levels may also maintain the half-life of effective IL-6, as demonstrated previously (15).…”

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confidence: 83%

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

Wunderlich

Delić

Behnke

et al. 2012

The Journal of Immunology

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Circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mouse models, but the impact of IL-6 classic signaling through membrane IL-6Rα, as well as IL-6 trans-signaling through soluble IL-6Rα, on the outcome of malaria has remained unknown. In this study, we created IL-6Rα–deficient mice that exhibit a 50% survival of otherwise lethal blood-stage malaria of the genus Plasmodium chabaudi. Inducing IL-6 trans-signaling by injection of mouse recombinant soluble IL-6Rα in IL-6Rα–deficient mice restores the lethal outcome to malaria infection. In contrast, inhibition of IL-6 trans-signaling via injection of recombinant sGP130Fc protein in control mice results in a 40% survival rate. Our data demonstrate that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality in mice, preceded by an increased inflammatory response. Therefore, inhibition of IL-6 trans-signaling may serve as a novel promising therapeutic basis to combat malaria.

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confidence: 83%

“…The mode of IL-6 action is complex (4,13,14). IL-6 signals through the specificity-defining membrane IL-6Ra, which requires the recruitment of two chains of the membrane receptor GP130 for signal transduction to activate the JAK/ STAT pathway.…”

mentioning

confidence: 99%

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

Wunderlich

Delić

Behnke

et al. 2012

The Journal of Immunology

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“…55,56 Through both classic and trans-signaling pathways, described in the cornea during inflammation, 57 IL-6 signals via the tyrosine-protein kinase JAK2 and STAT3 to modulate the transcription of genes linked to the cell cycle, inflammation, apoptosis, cytokine signaling, and lipid metabolism. 58 Local neutralization of IL-6 revealed IL-6 functions as one of the mediators of nerve degeneration because its deficiency in the infected cornea resulted in partial preservation of corneal sensitivity, which correlated with modest retention of fine subbasal bundles of nerves.…”

Section: Hsv-1 Inflammation and Corneal Nervesmentioning

confidence: 99%

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Chucair-Elliott

Jinkins

Carr

et al. 2016

The American Journal of Pathology

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Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis characterized by decreased corneal sensation because of damage to the corneal sensory fibers. We and others have reported regression of corneal nerves during acute HSV-1 infection. To determine whether denervation is caused directly by the virus or indirectly by the elicited immune response, mice were infected with HSV-1 and topically treated with dexamethasone (DEX) or control eye drops. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer and nerve network structure via immunohistochemistry. Corneas were assessed for viral content by plaque assay, leukocyte influx by flow cytometry, and content of chemokines and inflammatory cytokines by suspension array. DEX significantly preserved corneal nerve structure and sensitivity on infection. DEX reduced myeloid and T-cell populations in the cornea and did not affect viral contents at 4 and 8 days post infection. The elevated protein contents of chemokines and inflammatory cytokines on infection were greatly suppressed by DEX. Subconjunctival delivery of neutralizing antibody against IL-6 to infected mice resulted in partial preservation of corneal nerve structure and sensitivity. Our study supports a role for the immune response, but not local virus replication in the development of HSV-1einduced neurotrophic keratitis. IL-6 is one of the factors produced by the elicited inflammatory response to HSV-1 infection contributing to nerve regression.

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“…There are three activation mechanisms of the IL-6/gp130/JAK/STAT pathway, classical, transsignaling and cluster signaling. 13,14 Classical involves membrane-bound gp80, which attracts gp130 subunits and transduces the signal, while transsignaling utilizes sIL-6R/gp130 complex. IL-6 transsignalling regulates mostly pro-inflammatory reactions.…”

Section: Discussionmentioning

confidence: 99%

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Kwiatkowska-Borowczyk

Czerwińska

Mackiewicz

et al. 2018

OncoImmunology

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Allogeneic whole cell gene modified therapeutic melanoma vaccine (AGI-101H) comprising of two melanoma cell lines transduced with cDNA encoding fusion protein composed of IL-6 linked with the soluble IL-6 receptor (sIL-6R), referred to as H6 was developed. H6 served as a molecular adjuvant, however, it has altered vaccine cells phenotype towards melanoma stem cells (MSC)-like with high activity of aldehyde dehydrogenase isoenzyme (ALDH1A1). AGI-101H was applied in advanced melanoma patients with non-resected and resected disease. In the adjuvant setting, it was combined with surgery in case of recurring metastases, which were surgically removed and vaccination continued. A significant fraction of AGI-101H treated melanoma patients is still alive (11–19 years). Out of 106 living patients, 39 were HLA-A2 positive and were the subject of the study. Immunization of melanoma patients resulted in the generation of cytotoxic CD8+ T cells specific for ALDH1A1, which were detected in circulation by HLA-A0201 MHC dextramers loaded with ALDH1A188-96(LLYKLADLI) peptide. Phenotypically they were central memory CD8+ T cells. Re-stimulation with ALDH1A188-96 ex vivo resulted in IFN-γ secretion and cells degranulation. Following each vaccine dose administration, the number of ALDH1A1-CD8+ T cells increased in circulation and returned to the previous level until next dose injection (one month). ALDH1A1-CD8+ T cells were also found, however in the lower number than in vaccinated patients, in the circulation of untreated melanoma with stage IV but were not found in stage II or III and healthy donors. Specific anti-ALDH1 antibodies were present in treated patients. Long-term survival suggests immuno-targeting of MSC in treated patients.

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Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration

Cited by 74 publications

References 98 publications

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

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

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

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