Making anti-cytokine therapy more selective: Studies in mice

Drutskaya, Marina S.; Efimov, Grigory A.; Astrakhantseva, Irina V.; Kruglov, Andrey; Nedospasov, Sergei A.

doi:10.1016/j.cyto.2016.08.022

Cited by 15 publications

(10 citation statements)

References 61 publications

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“…TNF-α, IL-1β, and IL-6 are key players in the regulation of immune response and inflammatory processes during infection [28]. In the central nervous system, TNF-α and IL-1β regulate synaptic plasticity, neurodegeneration, learning, and memory [29-32].…”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Coss²

2019

Neuroendocrinology

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Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1–7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1–7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.

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Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Coss²

2019

Neuroendocrinology

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“…A large number of compounds are reported to inhibit the release of extracellular cytokines or chemokines, many of which suppress the expression levels by targeting the inflammatory signaling cascade [38][39]. However, for some diseases such as asthma and diabetic retinopathy, abnormal post-transcriptional regulation is key [40][41].…”

Section: Discussionmentioning

confidence: 99%

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Kase

Terashima

Ohta

et al. 2020

Preprint

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Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10.CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases. Significance statementIn this study, we identified a histone deacetylase inhibitor CUDC-907 as a potential effective compound for ameliorating overproduction of inflammatory chemokines in an autoinflammatory disease named Nakajo-Nishimura syndrome. We performed high-throughput screening using pluripotent stem cell-derived monocytic cell lines. Our data prove the validity of screening system as a versatile platform for seeking candidate compounds for the treatment of congenital immunological disorders associated with monocytic lineage cells.

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“…С использованием уникальных мышей, созданных с помощью технологий редактирования генома, были изучены особенности протекания ýкспериментальных заболеваний, таких как коллаген-индуцированный артрит, ýкспериментальный аутоиммунный ýнцефаломиелит (ЭАЭ), ýкспериментальный колит, ýкспериментальные бактериальные инфекции, а также рак кожи и рак кишечника. В некоторых из ýтих моделей нами была впервые установлена патогенная роль TNF из ограниченного числа клеточных источников, в частности из миелоидных клеток [6,7]. По крайней мере в двух моделях заболеваний -Bulletin of Siberian Medicine.…”

Section: Tnf Lt рецепторы Tnf и анти-Tnf терапияunclassified

“…Считается, что TNF рецептор 2 (TNFR2, p75) предпочтительно узнает именно трансмембранную форму TNF, которая отвечает только за некоторые иммунорегуляторные свойства TNF [8]. Мы предполагаем, что защитный ýффект TNF, продуцируемого Т-клетками при артрите, связан, по крайней мере, частично с контролем патогенных популяций Тн1 и Тн17 CD4+ Т-клеток в периферических лимфоидных органах, а не в суставах, где развиваются патологические процессы [7].…”

Section: Tnf Lt рецепторы Tnf и анти-Tnf терапияunclassified

Cytokines, reverse genetics and anti-cytokine therapy

et al. 2019

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Cytokines comprise the molecular language of communication between the cells, which is needed to maintain the homeostatic functions of the body (including the immune system) and mediate various diseases. Many aspects of inflammation, autoimmune diseases and neoplasia are associated with cytokine signaling through specific receptors. The establishment of new physiological functions of “old” cytokines and understanding the molecular and cellular mechanisms of their involvement in disease pathogenesis, as well as the search for new therapeutic targets and development of innovative approaches to anti-cytokine therapy, present a fundamental problem. When assessing the tremendous success of anti-cytokine therapy in treatment of certain autoimmune diseases, we should not forget that (a) this treatment does not eliminate the causes of the disease:autoreactive T-cell clones; and that (b) less than half of the patients respond to this therapy; and that (c) anti-cytokine therapy has serious side effects.

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Making anti-cytokine therapy more selective: Studies in mice

Cited by 15 publications

References 61 publications

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Cytokines, reverse genetics and anti-cytokine therapy

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