scholarly journals Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes

iScience ◽  
2020 ◽  
Vol 23 (8) ◽  
pp. 101433
Author(s):  
Thomas C. Chamberlain ◽  
Sylvia T. Cheung ◽  
Jeff S.J. Yoon ◽  
Andrew Ming-Lum ◽  
Bernd R. Gardill ◽  
...  
Keyword(s):  
Small Molecule ◽  
Interleukin 10 ◽  
Anti Inflammatory ◽  
Allosteric Regulators

scholarly journals Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-Inflammatory Effects Through SHIP1/STAT3 Complexes

2020 ◽  
Author(s):  
Thomas C. Chamberlain ◽  
Sylvia T. Cheung ◽  
Jeff S.J. Yoon ◽  
Andrew Ming-Lum ◽  
Bernd R. Gardill ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Interleukin 10 ◽  
Docking Studies ◽  
Mechanisms Of Action ◽  
Drug Binding ◽  
Inositol Polyphosphate ◽  
Anti Inflammatory ◽  
Allosteric Regulators ◽  
Inflammatory Action ◽  
Pro Inflammatory Cytokines

ABSTRACTThe anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells, and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1, and provide a rationale for use of allosteric SHIP1-activating compounds which mimic the beneficial anti-inflammatory actions of IL10.

HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway

2021 ◽  
Author(s):  
Yong Fu ◽  
Gailing Ma ◽  
Yuqian Zhang ◽  
Wenli Wang ◽  
Tongguo Shi ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Experimental Colitis ◽  
Underlying Mechanism ◽  
Interleukin 10 ◽  
Camp Response Element Binding ◽  
Cellular Level ◽  
Trinitrobenzene Sulfonic Acid ◽  
Murine Colitis ◽  
Anti Inflammatory

Abstract Background Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that plays a pivotal role in maintaining mucosal immune homeostasis. As a novel synthetic inhibitor of salt-inducible kinases (SIKs), HG-9-91-01 can effectively enhance IL-10 secretion at the cellular level, but its in vivo immunoregulatory effects remain unclear. In this study, we investigated the effects and underlying mechanism of HG-9-91-01 in murine colitis models. Methods The anti-inflammatory effects of HG-9-91-01 were evaluated on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-, dextran sulfate sodium–induced colitis mice, and IL-10 knockout chronic colitis mice. The in vivo effector cell of HG-9-91-01 was identified by fluorescence-activated cell sorting and quantitative real-time polymerase chain reaction. The underlying mechanism of HG-9-91-01 was investigated via overexpressing SIKs in ANA-1 macrophages and TNBS colitis mice. Results Treatment with HG-9-91-01 showed favorable anticolitis effects in both TNBS- and DSS-treated mice through significantly promoting IL-10 expression in colonic macrophages but failed to protect against IL-10 KO murine colitis. Further study indicated that HG-9-91-01 markedly enhanced the nuclear level of cAMP response element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3), whereas treatment with lentiviruses encoding SIK protein markedly decreased the nuclear CRTC3 level in HG-9-91-01–treated ANA-1 macrophages. In addition, intracolonic administration with lentiviruses encoding SIK protein significantly decreased the nuclear CRTC3 level in the lamina propria mononuclear cells and ended the anti-inflammatory activities of HG-9-91-01. Conclusions We found that HG-9-91-01 promoted the IL-10 expression of colonic macrophages and exhibited its anticolitis activity through the SIK/CRTC3 axis, and thus it may represent a promising strategy for inflammatory bowel disease therapy.

scholarly journals AB0069 LORECIVIVINT (SM04690), AN INTRA-ARTICULAR, SMALL-MOLECULE CLK/DYRK1A INHIBITOR THAT MODULATES THE WNT PATHWAY, AS A POTENTIAL TREATMENT FOR MENISCAL INJURIES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1335.2-1335
Author(s):  
T. Seo ◽  
V. Deshmukh ◽  
Y. Yazici
Keyword(s):  
Small Molecule ◽  
Rat Model ◽  
Wnt Pathway ◽  
Ex Vivo ◽  
Meniscal Tear ◽  
Knee Oa ◽  
Meniscus Degeneration ◽  
Anti Inflammatory ◽  
Meniscal Damage

Background:Meniscal injuries, associated with pain, stiffness, and localized swelling, are the most common pathology of the knee with a prevalence of 61 per 100,000.1Meniscal damage is a frequent finding on MRI images of knee osteoarthritis (OA)2; while a meniscal tear can lead to knee OA, knee OA can also lead to a spontaneous meniscal tear.3Efforts to repair meniscal damage have been largely unsuccessful and do not prevent the progression of degenerative changes that lead to knee OA.4The Wnt signaling pathway has been shown to be regulated during meniscal development,5,6suggesting that manipulation of this pathway may influence the regenerative capacity of the meniscus. Lorecivivint (LOR; SM04690) is an intra-articular (IA), small-molecule CLK/DYRK1A inhibitor that modulates the Wnt pathway.Objectives:LOR was evaluated in preclinical studies to determine its protective and anabolic effects in ex vivo explants and in a rat model of chemically induced inflammatory meniscus degeneration.Methods:Effects of LOR (30 nM) on expression of matrix metalloproteinases (MMPs) in cultured rat menisci treated with IL-1B were measured by qPCR. In vivo, LOR activity was evaluated in a rat model of monosodium iodoacetate (MIA) injection-induced inflammatory meniscus degeneration. A single IA injection of MIA was immediately followed by a single IA injection of LOR (0.3 ug) or vehicle. Knees were harvested on Days 1, 4, and 11 and menisci were isolated. Anti-inflammatory effects were evaluated by measuringTNFAandIL6expression by qPCR. Meniscus protection was evaluated by qPCR for MMPs and aggrecanase and anabolic effects by qPCR for collagens.Results:In ex vivo meniscal explants, LOR inhibited expression ofMMP1,MMP3, andMMP13compared to DMSO (P<0.01). In vivo, LOR significantly decreased expression of these MMPs and aggrecanase (P<0.05) compared to vehicle in the rat model of inflammatory meniscus degeneration at Day 4 after MIA injection. In addition, LOR reduced expression of inflammatory cytokinesTNFAandIL6at Day 4 compared to vehicle. Finally, LOR increased expression of collagen types I, II, and III at Day 11 after MIA injection.Conclusion:LOR exhibited protective effects in the meniscus ex vivo and in vivo by reducing the expression of catabolic enzymes compared to control. Anti-inflammatory effects of LOR were demonstrated by inhibition of inflammatory cytokine expression. Compared to vehicle, LOR increased expression of collagens in vivo, indicating potential meniscal anabolic effects. These data support further investigation of LOR as a potential disease-modifying therapy for meniscal injuries.References:[1]Logerstedt D and Snyder-Mackler L.J Orthop Sports Phys Ther. 2010[2]Englund M, et al.Rheum Dis Clin North Am. 2009[3]Englund M, et al.Radiol Clin North Am. 2009[4]von Lewinski, et al.Knee Surg Sports Traumatol Arthrosc. 2007[5]Pazin DE, et al.ORS 2012 Annual Meeting. Paper No. 0221[6]Pazin DE, et al.Dev Dyn. 2012Disclosure of Interests:Tim Seo Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Vishal Deshmukh Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Yusuf Yazici Shareholder of: Samumed, LLC, Grant/research support from: Bristol-Myers Squibb, Celgene, and Genentech, Consultant of: Celgene and Sanofi, Employee of: Samumed, LLC

scholarly journals Dual Role of Interleukin-10 in Murine NZB/W F1 Lupus

2021 ◽  
Vol 22 (3) ◽  
pp. 1347
Author(s):  
Anaïs Amend ◽  
Natalie Wickli ◽  
Anna-Lena Schäfer ◽  
Dalina T. L. Sprenger ◽  
Rudolf A. Manz ◽  
...  
Keyword(s):  
B Cell ◽  
Disease Model ◽  
Interleukin 10 ◽  
Immune Functions ◽  
Murine Lupus ◽  
Anti Inflammatory ◽  
In Vivo Effects

As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target.

scholarly journals Tobacco Exposure by Various Modes May Alter Proinflammatory (IL-12) and Anti-Inflammatory (IL-10) Levels and Affects the Survival of Prostate Carcinoma Patients: An Explorative Study in North Indian Population

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Shailendra Dwivedi ◽  
Apul Goel ◽  
Sanjay Khattri ◽  
Anil Mandhani ◽  
Praveen Sharma ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Prostate Carcinoma ◽  
Interleukin 10 ◽  
Interleukin 12 ◽  
Tobacco Exposure ◽  
Statistical Tool ◽  
Cytokine Levels ◽  
Test Graph ◽  
Anti Inflammatory ◽  
Alcohol Users

Objective. Inflammation is an important hallmark of all cancers and net inflammatory response is determined by a delicate balance between pro- and anti-inflammatory cytokines, which may be affected by tobacco exposure, so the present study was designed to explore the effect of various modes of tobacco exposure on interleukin-12 (IL-12) and interleukin-10 (IL-10) inflammatory cytokine levels and survival in prostate carcinoma (PCa) patients.Methods. 285 cancer patients and equal controls with 94 BPH (benign prostatic hyperplasia) were recruited; baseline levels of serum IL-12 and IL-10 were measured and analyzed in various tobacco exposed groups by appropriate statistical tool. Five-year survivals of patients were analyzed by Log-rank (Mantel-Cox) test (graph pad version 5).Results. The expression of serum proinflammatory (IL-12) and anti-inflammatory (IL-10) cytokines was correlated with tobacco exposed group as smokers, chewers, and alcohol users have shown significantly higher levels (P<0.001) with significantly lower median survivals (27.1 months, standard error = 2.86, and 95% CI: 21.4–32.62); than nonusers. Stages III and IV of tobacco addicted patients have also shown significantly increased levels of IL-12 and IL-10.Conclusions. IL-12 and IL-10 seem to be affected by various modes of tobacco exposure and inflammation also affects median survival of cancer patients.

scholarly journals Regulation of the Anti-Inflammatory Cytokines Interleukin-4 and Interleukin-10 during Pregnancy

2014 ◽  
Vol 5 ◽  
Author(s):  
Piyali Chatterjee ◽  
Valorie L. Chiasson ◽  
Kelsey R. Bounds ◽  
Brett M. Mitchell
Keyword(s):  
Inflammatory Cytokines ◽  
Interleukin 10 ◽  
Interleukin 4 ◽  
Anti Inflammatory

Association of interleukin-10 promoter polymorphisms with serofast state after syphilis treatment

2018 ◽  
Vol 95 (3) ◽  
pp. 163-168 ◽  
Author(s):  
Maciej Pastuszczak ◽  
Bogdan Jakiela ◽  
Anna Wojas-Pelc
Keyword(s):  
Immune Response ◽  
Interleukin 10 ◽  
Control Group ◽  
Serological Response ◽  
Promoter Polymorphisms ◽  
Related Factors ◽  
Adequate Treatment ◽  
Early Syphilis ◽  
Inflammatory Immune Response ◽  
Anti Inflammatory

ObjectivesRecent studies suggested that upregulation of anti-inflammatory immune response during early syphilis may be associated with persistence of Treponema pallidum infection despite adequate treatment, resulting in a serofast state. The objective of this study was to determine whether enhanced interleukin (IL)-10-related response during early T. pallidum infection increased the risk of serofast syphilis.MethodsTwo IL10 gene promoter polymorphisms affecting IL-10 production (−1082A>G [rs1800896], −592C>A [rs1800872]) and serum levels of IL-10 were measured in 80 patients with early syphilis before and 6 months after penicillin treatment and in 24 healthy volunteers (control group).ResultsAfter 6 months, patients were stratified based on serological response into two groups: (1) serofast state (n = 28) and (2) serologically cured (n = 52). Pretreatment and post-treatment serum IL-10 levels were significantly higher in patients who remained serofast compared with those who had a serological cure (p<0.001). The GG genotype of the −1082A>G (rs1800896) polymorphism and the CC genotype of the −592C>A (rs1800872) polymorphism were significantly correlated with higher serum IL-10 levels. Moreover, the OR for remaining serofast for carriers of these genotypes was 16.2 (95% CI: 4.1 to 65.0, p<0.0001) and 2.9 (95% CI: 1.4 to 5.9, p=0.002), respectively.ConclusionsWe showed that a pronounced anti-inflammatory immune response may be an important predictor for the serofast state. Additionally, host-related factors such as polymorphisms of immune regulatory genes may influence the risk of remaining serofast after syphilis therapy.

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