Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10

Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo–electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rβ, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rβ binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8+ T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.

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ABIN-3: a Molecular Basis for Species Divergence in Interleukin-10-Induced Anti-Inflammatory Actions

Molecular and Cellular Biology ◽

10.1128/mcb.00223-07 ◽

2007 ◽

Vol 27 (13) ◽

pp. 4603-4616 ◽

Cited By ~ 39

Author(s):

Brian K. Weaver ◽

Erwin Bohn ◽

Barbi A. Judd ◽

M. Pilar Gil ◽

Robert D. Schreiber

Keyword(s):

Macrophage Activation ◽

Interleukin 10 ◽

Mononuclear Phagocytes ◽

Toll Like Receptor ◽

Monocytic Cells ◽

Proinflammatory Responses ◽

Anti Inflammatory ◽

Species Specific ◽

Anti Inflammatory Cytokine ◽

Necrosis Factor

ABSTRACT Whereas interleukin-10 (IL-10) is an anti-inflammatory cytokine known to regulate macrophage activation, its full mechanism of action remains incompletely defined. In a screen to identify novel IL-10-induced genes, we cloned the mouse ortholog of human ABIN-3 (also termed LIND). ABIN-3 expression was induced selectively by IL-10 in both mouse and human mononuclear phagocytes coordinately undergoing proinflammatory responses. In contrast to the previously characterized ABINs, mouse ABIN-3 was incapable of inhibiting NF-κB activation by proinflammatory stimuli. Generation and analysis of ABIN-3-null mice demonstrated that ABIN-3 is unnecessary for the anti-inflammatory effects of IL-10 as well as for proper negative regulation of NF-κB. Conversely, human ABIN-3 was capable of inhibiting NF-κB activation in response to signaling from Toll-like receptor, IL-1, and tumor necrosis factor. Enforced expression of human ABIN-3 in human monocytic cells suppressed the cytoplasmic degradation of IκBα, the activation of NF-κB, and the induction of proinflammatory genes. Comparative sequence analyses revealed that mouse ABIN-3 lacks a complete ABIN homology domain, which was required for the functional activity of human ABIN-3. ABIN-3 is, thus, an IL-10-induced gene product capable of attenuating NF-κB in human macrophages yet is inoperative in mice and represents a basis for species-specific differences in IL-10 actions.

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Prevention of lipopolysaccharide-induced CD11b+ immune cell infiltration in the kidney: role of AT2 receptors

Bioscience Reports ◽

10.1042/bsr20190429 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 1

Author(s):

Sanket Patel ◽

Isha Dhande ◽

Elizabeth Alana Gray ◽

Quaisar Ali ◽

Tahir Hussain

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Interleukin 10 ◽

Conditioned Media ◽

Cell Infiltration ◽

Low Grade ◽

Immune Cell Infiltration ◽

Anti Inflammatory

AbstractImmune cell infiltration plays a central role in mediating endotoxemic acute kidney injury (AKI). Recently, we have reported the anti-inflammatory and reno-protective role of angiotensin-II type-2 receptor (AT2R) activation under chronic low-grade inflammatory condition in the obese Zucker rat model. However, the role of AT2R activation in preventing lipopolysaccharide (LPS)-induced early infiltration of immune cells, inflammation and AKI is not known. Mice were treated with AT2R agonist C21 (0.3 mg/kg), with and without AT2R antagonist PD123319 (5 mg/kg) prior to or concurrently with LPS (5 mg/kg) challenge. Prior-treatment with C21, but not concurrent treatment, significantly prevented the LPS-induced renal infiltration of CD11b+ immune cells, increase in the levels of circulating and/or renal chemotactic cytokines, particularly interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) and markers of renal dysfunction (blood urea nitrogen and albuminuria), while preserving anti-inflammatory interleukin-10 (IL-10) production. Moreover, C21 treatment in the absence of LPS increased renal and circulating IL-10 levels. To investigate the role of IL-10 in a cross-talk between epithelial cells and monocytes, we performed in vitro conditioned media (CM) studies in human kidney proximal tubular epithelial (HK-2) cells and macrophages (differentiated human monocytes, THP-1 cells). These studies revealed that the conditioned-media derived from the C21-treated HK-2 cells reduced LPS-induced THP-1 tumor necrosis factor-α (TNF-α) production via IL-10 originating from HK-2 cells. Our findings suggest that prior activation of AT2R is prophylactic in preventing LPS-induced renal immune cell infiltration and dysfunction, possibly via IL-10 pathway.

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Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist

eLife ◽

10.7554/elife.65777 ◽

2021 ◽

Vol 10 ◽

Author(s):

Caleb R Glassman ◽

Leon Su ◽

Sonia S Majri-Morrison ◽

Hauke Winkelmann ◽

Fei Mo ◽

...

Keyword(s):

T Cells ◽

Interleukin 2 ◽

Cell Types ◽

Cell Type ◽

Partial Agonists ◽

State Dependent ◽

Response Thresholds ◽

Pleiotropic Actions ◽

Reduced Activity

Interleukin-2 is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells naturally differ in their sensitivity to IL-2 due to cell type and activation state-dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we used structure-based design to create and profile a series of IL-2 variants with the capacity to titrate maximum signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded Foxp3+ regulatory T cells with reduced activity on CD8+ T cells due to cell type-intrinsic differences in IL-2 signaling. IL-2-REH elicited cell type-dependent differences in gene expression and provided mixed therapeutic results: showing benefit in the in vivo mouse dextran sulfate sodium (DSS) model of colitis, but no therapeutic efficacy in a transfer colitis model. Our findings show that cytokine partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions, which may be generalizable to other cytokine and growth factor systems.

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

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab072 ◽

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.

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Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs

Drug Research ◽

10.1055/a-1291-7692 ◽

2021 ◽

Cited By ~ 1

Author(s):

Ashif Iqubal ◽

Farazul Hoda ◽

Abul Kalam Najmi ◽

Syed Ehtaishamul Haque

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Macrophage Activation ◽

Fatality Rate ◽

Cytokine Storm ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Disease Condition ◽

Inflammatory Drugs ◽

Anti Inflammatory

AbstractCoronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22031347 ◽

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.

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Immunometabolic Status of COVID-19 Cancer Patients

Physiological Reviews ◽

10.1152/physrev.00018.2020 ◽

2020 ◽

Vol 100 (4) ◽

pp. 1839-1850

Author(s):

A. Sica ◽

M. P. Colombo ◽

A. Trama ◽

L. Horn ◽

M. C. Garassino ◽

...

Keyword(s):

Cancer Patients ◽

Cancer Progression ◽

Macrophage Activation ◽

Viral Infections ◽

Immune Cell ◽

Case Series ◽

The United States ◽

Alternative Activation ◽

Nad Metabolism ◽

Increased Risk

Cancer patients appear to be more likely to be diagnosed with coronavirus disease 2019 (COVID-19). This is supported by the understanding of immunometabolic pathways that intersect patients with infection and cancer. However, data derived by case series and retrospective studies do not offer a coherent interpretation, since data from China suggest an increased risk of COVID-19, while data from the United States and Italy show a prevalence of COVID-19 in cancer patients comparable with the general population. Noteworthy, cancer and COVID-19 exploit distinct patterns of macrophage activation that promote disease progression in the most severe forms. In particular, the alternative activation of M2-polarized macrophages plays a crucial role in cancer progression. In contrast, the macrophage-activation syndrome appears as the source of M1-related cytokine storm in severe COVID-19 disease, thus indicating macrophages as a source of distinct inflammatory states in the two diseases, nonetheless as a common therapeutic target. New evidence indicates that NAMPT/NAD metabolism can direct both innate immune cell effector functions and the homeostatic robustness, in both cancer and infection. Moreover, a bidirectional relationship exists between the metabolism of NAD and the protective role that angiotensin converting enzyme 2, the COVID-19 receptor, can play against hyperinflammation. Within this immunometabolic framework, the review considers possible interference mechanisms that viral infections and tumors elicit on therapies and provides an overview for the management of patients with cancer affected by COVID-19, particularly for the balance of risk and benefit when planning normally routine cancer treatments and follow-up appointments.

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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

BioMed Research International ◽

10.1155/2014/158530 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 14

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2014.00253 ◽

2014 ◽

Vol 5 ◽

Cited By ~ 89

Author(s):

Piyali Chatterjee ◽

Valorie L. Chiasson ◽

Kelsey R. Bounds ◽

Brett M. Mitchell

Keyword(s):

Inflammatory Cytokines ◽

Interleukin 10 ◽

Interleukin 4 ◽

Anti Inflammatory

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Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-215125 ◽

2021 ◽

pp. 1-16

Author(s):

Staley A. Brod

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Cognitive Decline ◽

Immune Cell ◽

Inflammatory Responses ◽

Type I ◽

Type I Ifn ◽

Anti Inflammatory

Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

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