Elevated Interleukin-10 Levels in COVID-19: Potentiation of Pro-Inflammatory Responses or Impaired Anti-Inflammatory Action?

Astrocytes are glial cells that play an important role in neuroinflammation. Astrocytes respond to many pro-inflammatory stimuli, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4). Regulatory specificities of inflammatory signaling pathways are still largely unknown due to the ectodermal origin of astrocytes. Recently, we have shown that hyaluronic acid (HA) may form part of astrocyte inflammatory responses. Therefore, we tested 4-methylumbelliferone (4-MU), a specific inhibitor of HA synthesis, as a possible regulator of LPS-mediated responses. Rat primary astrocytes were treated with LPS with and without 4-MU and gene expression levels of inflammatory (interleukins 1β, (IL-1β), 6, (IL-6), tumor necrosis factor alpha TNFα,) and resolution interleukin 10 (IL-10) markers were evaluated via real-time PCR and western blot. The release of cytokines and HA was determined by ELISA. Oxylipin profiles were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. Our data show that 4-MU (i) has anti-inflammatory effects in the course of TLR4 activation, decreasing the cytokines level TNFα, IL-6 and IL-1β and increasing IL-10, (ii) downregulates prostaglandin synthesis but not via cyclooxygenases COX-1 and COX-2 pathways, (iii) modulates HA synthesis and decreases LPS-induced HA synthase mRNA expression (HAS-1, HAS-2) but does not have an influence on HAS-3, HYAL1 and HYAL2 mRNAs; (iv) the effects of 4-MU are predominantly revealed via JNK but not p38, ERK mitogen-activated protein kinases (MAPKs) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathways. For the first time, it is shown that 4-MU possesses the useful potential to regulate an inflammatory astrocyte response.

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Monocolonization of Germ-Free Mice withBacteroides fragilisProtects against Dextran Sulfate Sodium-Induced Acute Colitis

BioMed Research International ◽

10.1155/2014/675786 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Chien-Chao Chiu ◽

Yung-Hao Ching ◽

Yu-Chih Wang ◽

Ju-Yun Liu ◽

Yen-Peng Li ◽

...

Keyword(s):

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Inflammatory Responses ◽

Inflammatory Cells ◽

Interleukin 10 ◽

Myeloperoxidase Activity ◽

Acute Colitis ◽

Germ Free ◽

Intestinal Immune System ◽

Anti Inflammatory

Ulcerative colitis is inflammatory conditions of the colon caused by interplay of genetic and environmental factors. Previous studies indicated that the gut microflora may be involved in the colonic inflammation.Bacteroides fragilis(BF) is a Gram-negative anaerobe belonging to the colonic symbiotic. We aimed to investigate the protective role ofBFin a colitis model induced in germ-free (GF) mice by dextran sulfate sodium (DSS). GF C57BL/6JNarl mice were colonized withBFfor 28 days before acute colitis was induced by DSS.BFcolonization significantly increased animal survival by 40%, with less reduction in colon length, and decreased infiltration of inflammatory cells (macrophages and neutrophils) in colon mucosa following challenge with DSS. In addition,BFcould enhance the mRNA expression of anti-inflammatory-related cytokine such as interleukin 10 (IL-10) with polymorphism cytokineIL-17and diminish that of proinflammatory-related tumor necrosis factorαwith inducible nitric oxide synthase in the ulcerated colon. Myeloperoxidase activity was also decreased inBF-DSS mice. Taking these together, theBFcolonization significantly ameliorated DSS-induced colitis by suppressing the activity of inflammatory-related molecules and inducing the production of anti-inflammatory cytokines.BFmay play an important role in maintaining intestinal immune system homeostasis and regulate inflammatory responses.

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Alpha 1-antitrypsin ameliorates ventilator-induced lung injury in rats by inhibiting inflammatory responses and apoptosis

Experimental Biology and Medicine ◽

10.1177/1535370217740852 ◽

2017 ◽

Vol 243 (1) ◽

pp. 87-95 ◽

Cited By ~ 3

Author(s):

He Zhu ◽

Jianshuai He ◽

Jia Liu ◽

Xin Zhang ◽

Fengyun Yang ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Inflammatory Responses ◽

Treatment Options ◽

Weight Ratio ◽

Interleukin 10 ◽

Male Rats ◽

Ventilator Induced Lung Injury ◽

Anti Inflammatory ◽

Alpha 1 Antitrypsin

Mechanical ventilation is extensively used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). The present study investigated the protective effect of alpha 1-antitrypsin (AAT) on VILI. Adult male rats were subjected to sham, ventilation + saline, or ventilation + AAT treatment and lung injuries were evaluated. Peripheral blood and bronchoalveolar lavage fluid (BALF) were obtained to assess systemic and local inflammatory responses, respectively. Mechanical ventilation resulted in lung injury, as evidenced by histological abnormalities as well as elevations in PaO2/FiO2 ratio, the wet-to-dry weight ratio, and the BALF level of proteins. The intravenous administration of AAT significantly improved these parameters of lung function, suggesting a protective role of AAT in VILI. Mechanistically, ventilator-induced inflammation was effectively reduced by AAT, as evidenced by decreases in BALF neutrophil counts, BALF cytokines, and serum adhesion factors. In contrast, anti-inflammatory interleukin-10 in BALF was increased in response to AAT. AAT treatment also inhibited the expression of nuclear factor-κB, Bax, and cleaved caspase-3 while promoting Bcl-2 expression in ventilator-injured lung tissues. AAT treatment can ameliorate VILI by inhibiting inflammatory mediator production and apoptosis. Impact statement Mechanical ventilation has been commonly used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). Few effective treatment options are currently available to reduce VILI. Alpha 1-antitrypsin (AAT) is an inhibitor of serine protease with anti-inflammatory and antiapoptotic properties, suggesting a possible role in attenuating lung injury. The present study demonstrates that AAT inhibits the development of VILI by modulating inflammation- and apoptosis-related protein expression. Therefore, AAT may be a novel therapeutic agent for acute respiratory distress syndrome patients undergoing mechanical ventilation.

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Evaluation of Anti-Inflammatory Activity of Pseudananas macrodontes (Morr.) Harms (Bromeliaceae) Fruit Extract in Rats

Zeitschrift für Naturforschung C ◽

10.1515/znc-2013-11-1203 ◽

2013 ◽

Vol 68 (11-12) ◽

pp. 445-452 ◽

Cited By ~ 2

Author(s):

María E. Errasti ◽

Néstor O. Caffini ◽

Lilian E. Pelzer ◽

Alejandra E. Rotelli

Keyword(s):

Proteolytic Activity ◽

Inflammatory Responses ◽

Complementary Therapy ◽

Ananas Comosus ◽

Inflammatory Models ◽

Rat Paw Edema ◽

Cysteine Endopeptidases ◽

Anti Inflammatory ◽

Main Components ◽

Inflammatory Action

Several species of the family Bromeliaceae are characterized by the production of proteases in unusual amounts, especially in fruits. Bromelain, an extract rich in cysteine endopeptidases obtained from Ananas comosus L., and a few other proteases have been used as anti-inflammatory agents for some years, but bromelain is still mainly being used as alternative and/or complementary therapy to the treatment with glucocorticoids, nonsteroidal antirheumatics, and immunomodulators. In this study, the anti-inflammatory action of a partially purified extract from Pseudananas macrodontes (Morr.) Harms fruits (PPEPm) is presented, whose main components are cysteine endopeptidases. The effect of PPEPm was assessed in carrageenan-induced and serotonin-induced rat paw edema, as well as in the cotton pellet granuloma model. Doses with equal proteolytic activity of PPEPm and bromelain produced significantly similar anti-inflammatory responses in the acute inflammatory models assayed, supporting the hypothesis that proteolytic activity could be responsible for the anti-inflammatory action. On the contrary, comparable anti-inflammatory effects of PPEPm and bromelain in the chronic inflammatory assay required a much lower proteolytic activity content of PPEPm, which could be due to a differential affinity for the protein target involved in this process.

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The Strand Specific Regulation of miR-155-3p in Response to Lipopolysaccharide and Interleukin-10 Stimulation Requires FUBP1 Protein

10.20944/preprints202111.0272.v1 ◽

2021 ◽

Author(s):

Jeff S. J. Yoon ◽

Abdulwadood Baksh ◽

Thomas C. Chamberlain ◽

Alice L-F. Mui

Keyword(s):

Inflammatory Cytokine ◽

Inflammatory Responses ◽

Interleukin 10 ◽

Activated Macrophages ◽

Anti Inflammatory ◽

Specific Regulation ◽

Anti Inflammatory Cytokine

MicroRNA-155 (miR-155) expression promotes inflammatory responses in macrophages. Activation of macrophages with lipopolysaccharide (LPS) elevates miR-155, while the anti-inflammatory cytokine interleukin-10 (IL10) reduces miR-155 levels. MiR-155 exists in two forms, miR-155-5p and miR-155-3p, produced from the precursor of miR-155 (pre-miR-155). MiR-155-5p is the most abundant strand in activated macrophages, but in response to LPS, the miR-155-3p level is upregulated first, followed by miR-155-5p later. We have previously identified CELF2 protein which interacts with pre-miR-155 and impairs miR-155-5p expression. We now show that CELF2 only regulates the miR-155-5p expression and that another protein FUBP1 controls miR-155-3p levels in response to LPS and IL10.

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267. Interleukin-10 inhibits TNFα synthesis and protects against LPS-induced miscarriage and preterm labour

Reproduction Fertility and Development ◽

10.1071/srb05abs267 ◽

2005 ◽

Vol 17 (9) ◽

pp. 109

Author(s):

S. A. Robertson ◽

R. J. Skinner ◽

A. S. Care

Keyword(s):

Fetal Growth ◽

Low Dose ◽

Inflammatory Responses ◽

Preterm Labour ◽

Fetal Loss ◽

Placental Tissue ◽

Interleukin 10 ◽

Null Mutant ◽

Anti Inflammatory ◽

In Pregnancy

The immune-deviating and anti-inflammatory cytokine interleukin-10 (IL-10) is expressed throughout pregnancy in the decidual and placental tissues. Mice with a null mutation in the IL-10 gene mice are fertile with no reduction in litter size, although fetal growth trajectories and placental structure are altered. IL-10 is known to terminate inflammatory responses and to limit inflammation-induced tissue pathology by inhibiting macrophage synthesis of tumor necrosis factor-α (TNFα). To investigate the anti-inflammatory role of IL-10 in pregnancy, the susceptibility of null mutant mice to low dose LPS-induced miscarriage and preterm labour has been evaluated. When IL-10 null mutant C57Bl/6 (IL-10–/–) and control (IL-10+/+) mice were given low dose E.coli LPS on d10 of pregnancy, IL-10 deficiency was associated with greater fetal loss with fewer mated IL-10–/– mice carrying viable fetuses at day 18 and increased rate of fetal resorption. In mice treated with LPS on day 17, preterm delivery within 24 h occurred in a higher proportion of IL-10–/– mice than IL-10+/+ mice. LPS induced very high and sustained TNFα and IL-6 content in serum, uterine and placental tissue in IL-10–/– mice, associated with upregulated mRNA expression of both cytokines in gestational tissues. These data show that IL-10 modulates placental resistance to inflammatory stimuli by down-regulating expression of the pro-inflammatory cytokines TNFα and IL-6. We conclude that IL-10 has a dual role in pregnancy, acting to regulate placental morphogenesis and fetal growth trajectory, and to protect against inflammation-induced miscarriage and preterm labour.

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Interleukin-10 and the regulation of mitogen-activated protein kinases: are these signalling modules targets for the anti-inflammatory action of this cytokine?

Cellular Signalling ◽

10.1016/s0898-6568(02)00075-x ◽

2003 ◽

Vol 15 (3) ◽

pp. 255-267 ◽

Cited By ~ 48

Author(s):

John J Haddad ◽

Nayef E Saadé ◽

Bared Safieh-Garabedian

Keyword(s):

Protein Kinases ◽

Interleukin 10 ◽

Mitogen Activated Protein Kinases ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Inflammatory Action

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Association of the anti inflammatory action of interleukin 10 with metalloproteinases and other inflammatory markers in acute coronary syndromes

Atherosclerosis Supplements ◽

10.1016/s1567-5688(02)80736-x ◽

2002 ◽

Vol 3 (2) ◽

pp. 225

Keyword(s):

Inflammatory Markers ◽

Acute Coronary Syndromes ◽

Interleukin 10 ◽

Coronary Syndromes ◽

Anti Inflammatory ◽

Inflammatory Action

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Gain-of-Function Mutation of Tristetraprolin Impairs Negative Feedback Control of Macrophages In Vitro yet Has Overwhelmingly Anti-Inflammatory Consequences In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.00536-16 ◽

2017 ◽

Vol 37 (11) ◽

Cited By ~ 3

Author(s):

John D. O'Neil ◽

Ewan A. Ross ◽

Michael L. Ridley ◽

Qize Ding ◽

Tina Tang ◽

...

Keyword(s):

Feedback Control ◽

Negative Feedback ◽

Inflammatory Responses ◽

Interleukin 10 ◽

Gain Of Function ◽

Negative Feedback Control ◽

Anti Inflammatory ◽

The Impact

ABSTRACT The mRNA-destabilizing factor tristetraprolin (TTP) binds in a sequence-specific manner to the 3′ untranslated regions of many proinflammatory mRNAs and recruits complexes of nucleases to promote rapid mRNA turnover. Mice lacking TTP develop a severe, spontaneous inflammatory syndrome characterized by the overexpression of tumor necrosis factor and other inflammatory mediators. However, TTP also employs the same mechanism to inhibit the expression of the potent anti-inflammatory cytokine interleukin 10 (IL-10). Perturbation of TTP function may therefore have mixed effects on inflammatory responses, either increasing or decreasing the expression of proinflammatory factors via direct or indirect mechanisms. We recently described a knock-in mouse strain in which the substitution of 2 amino acids of the endogenous TTP protein renders it constitutively active as an mRNA-destabilizing factor. Here we investigate the impact on the IL-10-mediated anti-inflammatory response. It is shown that the gain-of-function mutation of TTP impairs IL-10-mediated negative feedback control of macrophage function in vitro. However, the in vivo effects of TTP mutation are uniformly anti-inflammatory despite the decreased expression of IL-10.

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