More and more pleiotropy within the IL-6 family of cytokines.

Historically, cytokines belonging to the gp130 family bind to specific ligand-binding receptors that stimulate cell signaling through a receptor complex comprising gp130 or gp130 together with another structurally related signaling receptor. However, recent findings increasingly dispel these stereotypes and suggest that the receptor specificity of gp130-activating cytokines is less strict than originally assumed. Weitz et al.

A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling.

A poor maternal diet during pregnancy predisposes the infant to severe lower respiratory tract infections (sLRIs), which, in turn, increases childhood asthma risk; however, the underlying mechanisms remain poorly understood. Here, we show that the offspring of high-fat diet (HFD)-fed mothers (HFD-reared pups) developed an sLRI following pneumovirus inoculation in early life and subsequent asthma in later life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyperneutropoiesis in the liver and elevated inflammatory cytokine expression, most notably granulocyte-colony stimulating factor (G-CSF), interleukin-17A (IL-17A), IL-6 and soluble IL-6 receptor (sIL-6R) (indicative of IL-6 trans-signaling) in the circulation and multiple organs but most prominently the liver.

Effect of intravitreal injection of anti-interleukin (IL)-6 antibody in experimental autoimmune uveitis in mice.

Purpose: The aim of this study was to assess the functional and clinical impact of intravitreal administration of a neutralizing anti-IL-6 antibody in the treatment of experimental autoimmune uveitis (EAU) in mice.

Methods: EAU was induced in 17 female B10.RIII mice by administering Inter-Photoreceptor-Binding-Protein (IRBP) in complete Freund's adjuvant, followed by a boost with Pertussis toxin.

Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment.

Background: Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood.

Increased Expression of the Neuropeptides PACAP/VIP in the Brain of Mice with CNS Targeted Production of IL-6 Is Mediated in Part by Trans-Signalling.

Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown.

Idiopathic multicentric Castleman disease with marrow fibrosis and extramedullary hematopoiesis.

Background: Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans.

Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy.

Background: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects.

Activation of gp130 signaling in T cells drives T17-mediated multi-organ autoimmunity.

The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, , specifically targeted to T cells.

An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma.

Background: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma.

Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the mouse fed a high-fat diet.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa.

Dissecting Interleukin-6 Classic and Trans-signaling in Inflammation and Cancer.

Interleukin-6 (IL-6) is a cytokine synthesized by many cells in the human body. IL-6 binds to a membrane-bound receptor (IL-6R), which is only present on hepatocytes, some epithelial cells, and some leukocytes. The complex of IL-6 and IL-6R binds to the ubiquitously expressed receptor subunit gp130, which forms a homodimer and thereby initiates intracellular signaling, e.

EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells.

The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory.

The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation.

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues.

Targeting IL-6 trans-signalling: past, present and future prospects.

Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed 'mIL-6R') and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130.

Constitutive Activation of gp130 in T Cells Results in Senescence and Premature Aging.

IL-6 family members contribute to host defense through the stimulation of acute-phase signaling, hematopoiesis, immune reactions, and regenerative processes. To investigate essential mechanisms that are linked toward a constitutively activated gp130 signaling, we generated and characterized a mouse model that reflects a constitutive and cytokine-independent activation of JAK/STAT3 signaling by Lgp130 in CD4- and CD8-positive T cells. Lgp130 is an engineered form of gp130 in which dimerization and activation are forced by a leucine zipper.

Crosstalk between microbiome, regulatory T cells and HCA2 orchestrates the inflammatory response in a murine psoriasis model.

The organ-specific microbiome plays a crucial role in tissue homeostasis, among other things by inducing regulatory T cells (Treg). This applies also to the skin and in this setting short chain fatty acids (SCFA) are relevant. It was demonstrated that topical application of SCFA controls the inflammatory response in the psoriasis-like imiquimod (IMQ)-induced murine skin inflammation model.

The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

Background: The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates.

Methods: To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors.

Results: Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate.

Measuring the Effect of Off-Balancing Vectors on the Delivery of High-Quality CPR during Ambulance Transport: A Proof of Concept Study.

Aim: This study aims to demonstrate the feasibility of quantifying the off-balancing vectors experienced during ambulance transport and comparing them to high-quality cardiopulmonary resuscitation (HQ-CPR) metrics.

Methods: Ten participants completed a total of 20 evolutions of compression-only HQ-CPR in an ambulance driven in a manner that minimized or increased linear and angular off-balancing vectors. Linear and angular velocity, linear and angular acceleration, and linear jerk were recorded.

The Effect of Sustained Poor Air Quality on EMS Call Volume and Characteristics: A Time-Stratified Case-Crossover Study.

Objectives: As wildfires and air pollution become more common across the United States, it is increasingly important to understand the burden they place on public health. Previous studies have noted relationships between air quality and use of Emergency Medical Services (EMS), but until now, these studies have focused on day-to-day air quality. The goal of this study is to investigate the effect of sustained periods of poor air quality on EMS call characteristics and volume.

Blockade of the protease ADAM17 ameliorates experimental pancreatitis.

Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling.

Development of a model to measure the effect of off-balancing vectors on the delivery of high-quality CPR in a moving vehicle.

Aim: We sought to develop a model to measure the acceleration and jerk vectors affecting the performance of High-Quality Cardiopulmonary Resuscitation (HQ-CPR) during patient transport.

Methods: Three participants completed a total of eighteen rounds of compression only HQ-CPR in a moving vehicle. The vehicle was driven in a manner that either minimized or increased linear and angular vectors.

Tetraspanin 8 Subfamily Members Regulate Substrate-Specificity of a Disintegrin and Metalloprotease 17.

Ectodomain shedding is an irreversible process to regulate inter- and intracellular signaling. Members of the a disintegrin and metalloprotease (ADAM) family are major mediators of ectodomain shedding. ADAM17 is involved in the processing of multiple substrates including tumor necrosis factor (TNF) α and EGF receptor ligands.