Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development

Aqel, S.; Kraus, Emma; Jena, Nivedita; Kumari, Vandana; Granitto, Marissa; Mao, Liang; Farinas, Marissa F.; Zhao, Erin Y; Perottino, G; Pei, Wei; Lovett-Racke, Amy E.; Racke, Michael K.; Fuchs, James R.; Li, C; Yang, Yuhong

doi:10.1111/cei.13258

Cited by 25 publications

(18 citation statements)

References 38 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell culture supernatants were analyzed for cytokines. Sandwich ELISA was performed as previously described (43,44) with the following antibodies: IL-6 (capture: MP5-20F3; detection: MP5-32C11; BD Pharmingen), TNFα (capture: 6B8; detection: MP6-XT22; BioLegend), IL-1β (capture: B122; detection: Poly3138; BioLegend); IL-10 (capture: JES5-2A5; detection: SXC-1; BD Pharmingen), and IL-34 (capture: CO54-35; detection: Poly5193; BioLegend). In brief, ELISA plates were coated with a purified capture antibody, blocked, and incubated with culture supernatants overnight at 4 • C. The plates were washed, incubated with a biotinylated detection antibody, and cytokines were detected using avidin-peroxidase and TMB Chromogen Solution (Life Technologies).…”

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

Neuron-Specific Vitamin D Signaling Attenuates Microglia Activation and CNS Autoimmunity

et al. 2020

View full text Add to dashboard Cite

Low vitamin D during childhood is associated with an increased risk of developing multiple sclerosis (MS) as an adult. Given that vitamin D has anti-inflammatory properties, it has been postulated that the relationship between MS and low vitamin D is due to immune dysregulation. Since the vitamin D receptor (VDR) is expressed in many cell types, this study investigated an alternative hypothesis-neuron-specific VDR signaling induces anti-inflammatory molecules that protect the central nervous system from autoimmunity. Using media from neurons treated with calcitriol, the active form of vitamin D 3 , LPS-activated microglia had a reduction in pro-inflammatory molecules, and a reciprocal induction of anti-inflammatory molecules. Since IL-34 is critical to the homeostasis of microglia, and was previously shown to be induced in endothelial cells by vitamin D, we investigated IL-34 as the potential anti-inflammatory molecule induced in neurons by vitamin D. Treatment of LPS-activated microglia with IL-34 reduced pro-inflammatory cytokine production and enhanced the expression of anti-inflammatory transcripts. However, neutralizing IL-34 in vitamin D neuronal conditioned media only impacted IL-6 and not the broader anti-inflammatory phenotype of microglia. To mimic low vitamin D in children, we used a neuron-specific inducible mouse model in which VDR was partially deleted in juvenile mice. Partial deletion of VDR in neurons during early life resulted in exacerbated CNS autoimmunity in adult mice. Overall, the study illustrated that vitamin D signaling in neurons promotes an anti-inflammatory state in microglia, and low vitamin D in early life may enhance CNS autoimmunity.

show abstract

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

Neuron-Specific Vitamin D Signaling Attenuates Microglia Activation and CNS Autoimmunity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We thought that decreased serum vitamin D levels in IIM patients led to functional deficit of Treg cells, finally causing the progression of disease. The possible mechanism considered that activating the vitamin D pathway could be a mechanism to decrease STAT1 and 3 activation and inflammatory cytokine output (24), and then affect the functional of Treg cells (25).…”

Section: Discussionmentioning

confidence: 99%

Decreased Serum 25-(OH)-D Level Associated With Muscle Enzyme and Myositis Specific Autoantibodies in Patients With Idiopathic Inflammatory Myopathy

Cheng

Liang

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

ObjectivesTo determine whether there is serum vitamin D deficiency and the low levels of serum vitamin D are correlated with serological and immunological indexes in patients with idiopathic inflammatory myopathy (IIM).MethodsA total of 63 newly diagnosed patients with IIM, and 55 age- and sex- matched healthy controls were enrolled. Serum levels of 25-(OH)-D were measured by enzyme-linked immunosorbent assay. The correlations of 25-(OH)-D levels with disease indicators and T cell subsets were analyzed.ResultThe levels of serum 25-(OH)-D in IIM were significantly lower than those in healthy controls (9.36 ± 5.56 vs 26.56 ± 5.37 ng/ml, p<0.001). The levels of serum liver enzyme ALT and AST and muscle enzyme CK, CKMB, LDH and HBDH were elevated as deficiency of vitamin D. In addition, the serum 25-(OH)-D levels were negatively correlated to ALT (r = -0.408, p = 0.001) and AST (r = -0.338, p = 0.007). The 25-(OH)-D levels in IIM patients in presence of anti-Jo-1 were significantly lower than those in patients without anti-Jo-1 (5.24 ± 3.17 vs 9.32 ± 5.60 ng/ml; p = 0.037). Similar results were found in patients with or without anti-Mi-2 antibody. The serum 25-(OH)-D levels were positively associated with total T (r = 0.203, p = 0.012) and Treg cells (r = 0.331, p = 0.013). The patients with deficient levels of vitamin D were more likely to have heliotrope, gastrointestinal and liver involvement.ConclusionsVitamin D deficiency existed in IIM patients, which was significantly correlated with muscle enzyme, presence of anti-Jo-1 and anti-Mi-2 antibody, and the absolute numbers of total T and Treg cells in IIM. It is suggested that vitamin D may play an important role in the immunological pathogenesis of IIM.

show abstract

“…Therefore, the development of low-molecular weight inhibitors is highly demanded for their superiority in oral absorption, low toxicity, and low antigenicity. Despite the immense importance of this task and the invested efforts, the IL-6 axis-influencing compounds are only few [141][142][143][144][145][146][147][148][149].…”

Section: Other Small Molecules-experimental Drugsmentioning

confidence: 99%

Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19

Brábek

Jakubek

Vellieux

et al. 2020

IJMS

View full text Add to dashboard Cite

Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.

show abstract

Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development

Cited by 25 publications

References 38 publications

Neuron-Specific Vitamin D Signaling Attenuates Microglia Activation and CNS Autoimmunity

Neuron-Specific Vitamin D Signaling Attenuates Microglia Activation and CNS Autoimmunity

Decreased Serum 25-(OH)-D Level Associated With Muscle Enzyme and Myositis Specific Autoantibodies in Patients With Idiopathic Inflammatory Myopathy

Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19

Contact Info

Product

Resources

About