Faculty Opinions recommendation of Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo.

The fetal pituitary-adrenal axis plays a key role in the fetal response to intrauterine stress and in the timing of parturition. The fetal sheep adrenal gland is relatively refractory to stimulation in midgestation (90–120 days) before the prepartum activation, which occurs around 135 days gestation (term = 147 ± 3 days). The mechanisms underlying the switch from adrenal quiescence to activation are unclear. Therefore, we have investigated the expression of suppressor of cytokine signaling-3 (SOCS-3), a putative inhibitor of tissue growth in the fetal sheep adrenal between 50 and 145 days gestation and in the adrenal of the growth-restricted fetal sheep in late gestation. SOCS-3 is activated by a range of cytokines, including prolactin (PRL), and we have, therefore, determined whether PRL administered in vivo or in vitro stimulates SOCS-3 mRNA expression in the fetal adrenal in late gestation. There was a decrease ( P < 0.005) in SOCS-3 expression in the fetal adrenal between 54 and 133 days and between 141 and 144 days gestation. Infusion of the dopaminergic agonist, bromocriptine, which suppressed fetal PRL concentrations but did not decrease adrenal SOCS-3 mRNA expression. PRL administration, however, significantly increased adrenal SOCS-3 mRNA expression ( P < 0.05). Similarly, there was an increase ( P < 0.05) in SOCS-3 mRNA expression in adrenocortical cells in vitro after exposure to PRL (50 ng/ml). Placental and fetal growth restriction had no effect on SOCS-3 expression in the adrenal during late gestation. In summary, the decrease in the expression of the inhibitor SOCS-3 after 133 days gestation may be permissive for a subsequent increase in fetal adrenal growth before birth. We conclude that factors other than PRL act to maintain adrenal SOCS-3 mRNA expression before 133 days gestation but that acute elevations of PRL can act to upregulate adrenal SOCS-3 expression in the sheep fetus during late gestation.

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miR-155 accelerates proliferation of mouse hepatocytes during liver regeneration by directly targeting SOCS1

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00072.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. G443-G453 ◽

Cited By ~ 7

Author(s):

Xia Lin ◽

Li Chen ◽

Haiyan Li ◽

Yu Liu ◽

Yanhong Guan ◽

...

Keyword(s):

Cell Cycle ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Molecular Mechanisms ◽

Pharmacological Intervention ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Proliferation Of Hepatocytes

Liver regeneration after two-thirds partial hepatectomy (PH) is a clinically significant repair process for restoring proper liver architecture. Although microRNA-155 (miR-155) has been found to serve as a crucial microRNA regulator that controls liver cell function and proliferation, little is known about its specific role in the regenerating liver. Using a mouse model with miR-155 overexpression or miR-155 knockout, we investigated the molecular mechanisms of miR-155 in liver regeneration. We found a marked induction of miR-155 in C57BL/6 mice after PH. Furthermore, RL-m155 mice showed enhanced liver regeneration as a result of accelerated progression of hepatocytes into the cell cycle, mainly through an increase in cyclin levels. However, proliferation of hepatocytes was delayed in miR-155-deficient livers. Expression of suppressor of cytokine signaling 1 (SOCS1) was dramatically downregulated in the process of liver regeneration, and enhancement of SOCS1 contributed to impaired proliferation of hepatocytes. Additionally, in vitro and in vivo experiments showed that adenovirus- or adeno-associated virus-mediated overexpression of SOCS1 attenuated improved liver regeneration induced by miR-155 overexpression. Our study shows that miR-155 is a pro-proliferative regulator in liver regeneration by facilitating the cell cycle and directly targeting SOCS1. NEW & NOTEWORTHY Our findings suggest a microRNA-155 (miR-155)-mediated positive regulation pattern in liver regeneration. A series of in vivo and in vitro studies showed that miR-155 upregulation enhanced partial hepatectomy-induced proliferation of hepatocytes by promoting the cell cycle without inducing DNA damage or apoptosis. Suppressor of cytokine signaling 1, a target gene of miR-155, antagonized the proliferation-promoting effect of miR-155. Therefore, pharmacological intervention targeting miR-155 may be therapeutically beneficial in various liver diseases.

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MiR-142-3p Suppresses SOCS6 Expression and Promotes Cell Proliferation in Nasopharyngeal Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000430147 ◽

2015 ◽

Vol 36 (5) ◽

pp. 1743-1752 ◽

Cited By ~ 20

Author(s):

Xiaoming Qi ◽

Jianqiang Li ◽

Changbo Zhou ◽

Chunlei Lv ◽

Min Tian

Keyword(s):

Cell Proliferation ◽

Nasopharyngeal Carcinoma ◽

Cell Cycle Progression ◽

Therapeutic Strategy ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Cycle Progression ◽

Direct Target

Background/Aims: An increasing number of studies show that microRNAs (miRNAs) play crucial roles in nasopharyngeal carcinoma (NPC) tumorigenesis. The aim of our study was to investigate the biological roles and mechanisms of miR-142-3p in NPC. Methods: miR-142-3p expression was examined in NPC specimens and nasopharyngitis biopsy samples by quantitative real-time PCR. The biological functions of miR-142-3p were studied using a series of in vitro and in vivo approaches. Results: miR-142-3p is over-expressed in NPC tissues and cell lines. Knockdown of miR-142-3p significantly inhibited cell proliferation and cell cycle progression in vitro, and suppressed tumor growth in a mouse model. Suppressor of cytokine signaling 6 (SOCS6) was identified as a direct target of miR-142-3p, and miR-142-3p down-regulated the expression of SOCS6 by directly binding to its 3′untranslated region (UTR). Knockdown of SOCS6 abrogated the effects of miR-142-3p down-regulation. Conclusion: These findings indicate that miR-142-3p regulates NPC development by down-regulating SOCS6 expression and suggest that modulation of miR-142-3p expression could be a therapeutic strategy for NPC.

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IL-33 Attenuates Sepsis by Inhibiting IL-17 Receptor Signaling through Upregulation of SOCS3

Cellular Physiology and Biochemistry ◽

10.1159/000479836 ◽

2017 ◽

Vol 42 (5) ◽

pp. 1961-1972 ◽

Cited By ~ 9

Author(s):

Ran Lv ◽

Jinning Zhao ◽

Min Lei ◽

Dongju Xiao ◽

Yijin Yu ◽

...

Keyword(s):

Cecal Ligation ◽

Serum Levels ◽

Cytokine Signaling ◽

Experimental Sepsis ◽

Suppressor Of Cytokine Signaling ◽

Γδt Cells ◽

Negative Regulatory Role

Background/Aims: Sepsis is a systemic inflammatory response during infection. There are limited therapeutic options for sepsis patients. Interleukin (IL)-33 has been reported recently with a beneficial effect in mouse sepsis. Methods: In this study, we initiated a clinical study to measure serum levels of pro-inflammatory cytokines including IL-33 in sepsis patients. Next, we employed cecal ligation and puncture (CLP) to study the role of IL-33 during sepsis. To further dissect the molecular mechanism, we used in vivo knockout models and in vitro knockdown murine embryonic fibroblasts (MEFs) to investigate the cross-talk between IL-33 and IL-17 signaling, and to identify the potential downstream mediators. Results: IL-33 and IL-17 were upregulated in both clinical and experimental sepsis. In CLP, IL-33 (-/-) mice showed higher mortality rate, and IL-33 treatment improved the survival rate. Elevated proinflammatory cytokines in sepsis were related to IL-17 from γδT cells. IL-33 treatment suppressed production of these cytokines by targeting IL-17 signaling both in vivo and in vitro. Finally, IL-33 was shown to inhibit the IL-17 pathway via activating suppressor of cytokine signaling (SOCS)-3. Conclusion: Collectively, the results suggest that IL-33 plays a negative regulatory role in sepsis progression by inhibiting IL-17 pathway through activating SOCS3. This finding would inspire a new therapeutic strategy for treating sepsis.

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Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis

Journal of Immunology Research ◽

10.1155/2018/7897263 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 8

Author(s):

Martina Morelli ◽

Claudia Scarponi ◽

Laura Mercurio ◽

Francesco Facchiano ◽

Sabatino Pallotta ◽

...

Keyword(s):

Skin Lesions ◽

Janus Kinase ◽

Psoriatic Skin ◽

Epidermal Keratinocytes ◽

Cytokine Signaling ◽

Molecular Signaling ◽

Suppressor Of Cytokine Signaling ◽

Inflammatory Genes

IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes.

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Inhibition of Candida albicans in vivo and in vitro by antimicrobial peptides chromogranin A-N12 through microRNA-155/suppressor of cytokine signaling 1 axis

Bioengineered ◽

10.1080/21655979.2021.2017680 ◽

2022 ◽

Vol 13 (2) ◽

pp. 2513-2524

Author(s):

Xiaohua Li ◽

Qun Hu ◽

Qiong Lin ◽

Jianxiong Luo ◽

Junping Xu ◽

...

Keyword(s):

Candida Albicans ◽

Antimicrobial Peptides ◽

Chromogranin A ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

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Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury

Critical Care ◽

10.1186/s13054-021-03775-3 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Yang Jiao ◽

Ti Zhang ◽

Chengmi Zhang ◽

Haiying Ji ◽

Xingyu Tong ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Macrophage Activation ◽

Macrophage Polarization ◽

Cytokine Signaling ◽

Raw264.7 Macrophages ◽

M1 Macrophage ◽

Tnf Α

Abstract Background Polymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear. Methods Tumor necrosis factor-α (TNF-α), a key regulator of innate immunity in sepsis-related ALI, was used to stimulate PMNs from healthy C57BL/6J mice in vitro. Exosomes isolated from the supernatant were injected to C57BL/6J wild-type mice intraperitoneally (i.p.) and then examined for lung inflammation, macrophage (Mϕ) polarization and pyroptosis. In vitro co-culture system was applied where the mouse Raw264.7 macrophages or bone marrow-derived macrophages (BMDMs) were co-cultured with PMN-derived exosomes to further confirm the results of in vivo animal study and explore the potential mechanisms involved. Results Exosomes released by TNF-α-stimulated PMNs (TNF-Exo) promoted M1 macrophage activation after in vivo i.p. injection or in vitro co-culture. In addition, TNF-Exo primed macrophage for pyroptosis by upregulating NOD-like receptor 3 (NLRP3) inflammasome expression through nuclear factor κB (NF-κB) signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting suppressor of cytokine signaling (SOCS-1) and sirtuin 1 (SIRT1) in macrophages. Furthermore, intravenous administration of miR-30d-5p inhibitors significantly decreased TNF-Exo or cecal ligation and puncture (CLP)-induced M1 macrophage activation and macrophage death in the lung, as well as the histological lesions. Conclusions The present study demonstrated that exosomal miR-30d-5p from PMNs contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF-κB signaling. These findings suggest a novel mechanism of PMN-Mϕ interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients.

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Krüppel-like factor 3 (KLF3) suppresses NF-κB–driven inflammation in mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013114 ◽

2020 ◽

Vol 295 (18) ◽

pp. 6080-6091 ◽

Cited By ~ 1

Author(s):

Alexander J. Knights ◽

Lu Yang ◽

Manan Shah ◽

Laura J. Norton ◽

Gamran S. Green ◽

...

Keyword(s):

Transcription Factors ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Inflammatory Signals ◽

Health Burden ◽

Feedback Inhibitor ◽

Key Drivers ◽

Deficient Mice

Bacterial products such as lipopolysaccharides (or endotoxin) cause systemic inflammation, resulting in a substantial global health burden. The onset, progression, and resolution of the inflammatory response to endotoxin are usually tightly controlled to avoid chronic inflammation. Members of the NF-κB family of transcription factors are key drivers of inflammation that activate sets of genes in response to inflammatory signals. Such responses are typically short-lived and can be suppressed by proteins that act post-translationally, such as the SOCS (suppressor of cytokine signaling) family. Less is known about direct transcriptional regulation of these responses, however. Here, using a combination of in vitro approaches and in vivo animal models, we show that endotoxin treatment induced expression of the well-characterized transcriptional repressor Krüppel-like factor 3 (KLF3), which, in turn, directly repressed the expression of the NF-κB family member RELA/p65. We also observed that KLF3-deficient mice were hypersensitive to endotoxin and exhibited elevated levels of circulating Ly6C+ monocytes and macrophage-derived inflammatory cytokines. These findings reveal that KLF3 is a fundamental suppressor that operates as a feedback inhibitor of RELA/p65 and may be important in facilitating the resolution of inflammation.

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Suppressor of cytokine signaling-1 mimetic peptides attenuate lymphocyte activation in the MRL/lpr mouse autoimmune model

Scientific Reports ◽

10.1038/s41598-021-86017-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jatin Sharma ◽

Teresa D. Collins ◽

Tracoyia Roach ◽

Shiwangi Mishra ◽

Brandon K. Lam ◽

...

Keyword(s):

Intraperitoneal Administration ◽

Lymphocyte Activation ◽

Signal Propagation ◽

Skin Lesions ◽

Effector Memory ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Autoantibody Production ◽

Ifn Γ

AbstractAutoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

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