In VitroEffects of the Dicyclohexylammonium Salt of Hyperforin on Interleukin-6 Release in Different Experimental Models

AbstractConstitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC50] = 281nM), and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67nM) versus healthy donors (IC50 > 400nM). In a mouse model of JAK2V617F+ MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.

Download Full-text

Abstract 1632: Tie2-Deficient Mice Exhibit Increased Susceptibility to Endothelial Apoptosis, Arteriolar Muscularization, and Pulmonary Arterial Hypertension in Response to Interleukin-6

Circulation ◽

10.1161/circ.118.suppl_18.s_361-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Lakshmi Kugathasan ◽

Julie Basu Ray ◽

Yupu Deng ◽

Robin N Han ◽

Daniel Dumont ◽

...

Keyword(s):

Interleukin 6 ◽

Protective Role ◽

Experimental Models ◽

Receptor Expression ◽

Subcutaneous Injections ◽

Tie2 Receptor ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle ◽

Survival Signaling

Introduction: We have demonstrated downregulation in lung Tie2 receptor expression and activity in experimental models of PAH, implicating reduced Tie2 survival signaling in the pathogenesis of this disease. Therefore, we hypothesized that Tie2 deficiency would predispose to PAH due to increased endothelial cell (EC) apoptosis in response to environmental triggers. Methods: Adult male Tie2± or littermate WT mice received saline or interleukin-6 (IL-6) at a rate of 200ng/kg/day via subcutaneous injections for 1 or 2 weeks. Results: Significant elevation in RVSP (Fig.1 ) was observed in IL-6 treated Tie2± mice (31 ± 3mmHg) compared to saline-treated Tie2 ± mice (25 ± 1mmHg) and IL-6 treated WT mice (22 ± 1mmHg). Following 1 week of IL-6 treatment, increased pulmonary microvascular EC apoptosis was observed by TUNEL in Tie2± mice compared to WT (6.3 ± 0.3% vs. 0.9 ± 0.1%, respectively; p < 0.01). Furthermore, after 2 weeks, a significant increase in pulmonary microvascular muscularization by SMA staining (Fig.2 ) was seen in IL-6 treated Tie2±/mice compared to WT (36.4 ± 1.5% vs. 22.5 ± 1.1%, respectively; p < 0.01). Interestingly, Western blot analysis revealed a significant decrease in Angiopoietin-1 (Ang-1) level in the lung after 2 weeks of IL-6 treatment in Tie2± mice, and ELISA demonstrated a 60% decrease in Ang-1 secretion in vitro after incubation of pulmonary artery smooth muscle cells with IL-6 (p < 0.01). Conclusions: Tie2± mice demonstrated enhanced susceptibility to pulmonary EC apoptosis, increased muscularization, and PAH following chronic exposure to IL-6, supporting an important protective role for endogenous Tie2 signaling in the lung microvasculature. Figure 1. Increased RVSP in Tie2 +/+ mice following 2 weeks of IL-6 treatment (*P < 0.05 compared to Saline Tie2 +/+ ; † P < 0.01 compared to IL-6 WT) Figure 2. Increased pulmonary microvascular muscularization in Tie2 +/+ mice following 2 weeks of IL-6 treatment.

Download Full-text

Specific Increase in Joint Neutrophil Extracellular Traps and Its Relation to Interleukin 6 in Autoimmune Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22147633 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7633

Author(s):

Ayako Ohyama ◽

Atsumu Osada ◽

Hoshimi Kawaguchi ◽

Izumi Kurata ◽

Taihei Nishiyama ◽

...

Keyword(s):

Interleukin 6 ◽

Neutrophil Infiltration ◽

Experimental Models ◽

Neutrophil Extracellular Trap ◽

Neutrophil Chemotaxis ◽

Extracellular Traps ◽

Citrullinated Proteins ◽

Specific Increase ◽

Receptor Antibodies ◽

Citrullinated Protein

Neutrophils and their extracellular traps have been shown to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the detailed mechanisms in joints are still unclear, and their regulation remains to be solved. Here, we explored neutrophil extracellular trap (NET)osis in experimental models of arthritis and further investigated the effects of interleukin-6 (IL-6) inhibition in neutrophils and NETosis. In skins of peptide GPI-induced arthritis (pGIA), citrullinated protein was detected as well as citrullinated histone expression in immunized skin but this was not specific to pGIA. Citrullinated histone expression in pGIA joints was specific to pGIA and was merged with neutrophil elastase, suggesting NETosis. Neutrophils in joints tend to upregulate IL-6 receptors when compared with bone marrow neutrophils. Administration of mouse anti-IL-6 receptor antibodies in pGIA suppressed arthritis in association with a decrease in neutrophil infiltration and NETosis in joints. In the plasma of RA patients, citrullinated protein was significantly reduced after tocilizumab treatment. Our results suggest that IL-6 enhances neutrophil chemotaxis and NETosis in inflammatory joints and could be the source of citrullinated proteins.

Download Full-text

Understanding anemia of chronic disease

Hematology ◽

10.1182/asheducation-2015.1.14 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 14-18 ◽

Cited By ~ 24

Author(s):

Paula G. Fraenkel

Keyword(s):

Chronic Disease ◽

Interleukin 6 ◽

Severe Infection ◽

Epidemiologic Studies ◽

Experimental Models ◽

Adverse Outcomes ◽

Therapeutic Approaches ◽

Anemia Of Chronic Disease ◽

Iron Sequestration

Abstract The anemia of chronic disease is an old disease concept, but contemporary research in the role of proinflammatory cytokines and iron biology has shed new light on the pathophysiology of the condition. Recent epidemiologic studies have connected the anemia of chronic disease with critical illness, obesity, aging, and kidney failure, as well as with the well-established associations of cancer, chronic infection, and autoimmune disease. Functional iron deficiency, mediated principally by the interaction of interleukin-6, the iron regulatory hormone hepcidin, and the iron exporter ferroportin, is a major contributor to the anemia of chronic disease. Although anemia is associated with adverse outcomes, experimental models suggest that iron sequestration is desirable in the setting of severe infection. Experimental therapeutic approaches targeting interleukin-6 or the ferroportin–hepcidin axis have shown efficacy in reversing anemia in either animal models or human patients, although these agents have not yet been approved for the treatment of the anemia of chronic disease.

Download Full-text

ACE2 as therapeutic agent

Clinical Science ◽

10.1042/cs20200570 ◽

2020 ◽

Vol 134 (19) ◽

pp. 2581-2595

Author(s):

Qiuhong Li ◽

Maria B. Grant ◽

Elaine M. Richards ◽

Mohan K. Raizada

Keyword(s):

Therapeutic Agent ◽

Renin Angiotensin System ◽

Peptide Hormone ◽

Experimental Models ◽

Electrolyte Balance ◽

Ang Ii ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Overwhelming Evidence ◽

Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

Download Full-text