Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 729-738 ◽  
Author(s):  
Dominique Berrebi ◽  
Stefano Bruscoli ◽  
Nicolas Cohen ◽  
Arnaud Foussat ◽  
Graziella Migliorati ◽  
...  
Keyword(s):  
Gene Expression ◽  
Leucine Zipper ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Delayed Type Hypersensitivity ◽  
Glucocorticoid Treatment ◽  
Inflammatory Protein ◽  
Anti Inflammatory

Glucocorticoids and interleukin 10 (IL-10) prevent macrophage activation. In murine lymphocytes, glucocorticoids induce expression of glucocorticoid-induced leucine zipper (GILZ), which prevents the nuclear factor κB (NF-κB)–mediated activation of transcription. We investigated whether GILZ could account for the deactivation of macrophages by glucocorticoids and IL-10. We found that GILZ was constitutively produced by macrophages in nonlymphoid tissues of humans and mice. Glucocorticoids and IL-10 stimulated the production of GILZ by macrophages both in vitro and in vivo. Transfection of the macrophagelike cell line THP-1 with the GILZ gene inhibited the expression of CD80 and CD86 and the production of the proinflammatory chemokines regulated on activation normal T-cell expressed and secreted (CCL5) and macrophage inflammatory protein 1α (CCL3). It also prevented toll-like receptor 2 production induced by lipopolysaccharide, interferonγ, or an anti-CD40 mAb, as well as NF-κB function. In THP-1 cells treated with glucocorticoids or IL-10, GILZ was associated with the p65 subunit of NF-κB. Activated macrophages in the granulomas of patients with Crohn disease or tuberculosis do not produce GILZ. In contrast, GILZ production persists in tumor-infiltrating macrophages in Burkitt lymphomas. Therefore, GILZ appears to play a key role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL-10. Glucocorticoid treatment stimulates GILZ production, reproducing an effect of IL-10, a natural anti-inflammatory agent. The development of delayed-type hypersensitivity reactions is associated with the down-regulation of GILZ gene expression within lesions. In contrast, the persistence of GILZ gene expression in macrophages infiltrating Burkitt lymphomas may contribute to the failure of the immune system to reject the tumor.

scholarly journals Mesenchymal Stem Cell Therapy Ameliorates Metabolic Dysfunction and Restores Fertility in a PCOS Mouse Model Through Interleukin-10

2021 ◽  
Author(s):  
Rishi Man Chugh ◽  
Hang-soo Park ◽  
Abdeljabar El Andaloussi ◽  
Amro Elsharoud ◽  
Sahar Esfandyari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polycystic Ovary ◽  
Therapeutic Option ◽  
Interleukin 10 ◽  
Reproductive Age ◽  
Metabolic Dysfunction ◽  
Mesenchymal Stem Cell Therapy ◽  
Anti Inflammatory

Abstract Background: Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models.Methods: For in vitro experiment, we treated conditioned media from BM-hMSC to androgen producing H293R cells, and analyzed androgen producing gene expression. For in vivo experiment, BM-hMSC were implanted into Letrozole (LTZ) induced mouse PCOS model. BM-hMSC effect in androgen producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot, animal tissue assay (H&E staining), and fertility by pup delivery.Results: BM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improve in metabolic and reproductive markers in our PCOS model and able to restore fertility. Conclusion: Our study demonstrates for the first time the efficacy of intra-ovarian injection of BM-hMSC or its secretome to treat PCOS-related phenotypes, including both metabolic and reproductive dysfunction. This approach may represent a novel therapeutic option for women with PCOS. Our results suggest that BM-hMSC can reverse PCOS-induced inflammation through IL-10 secretion. BM-hMSC might be a novel and robust therapeutic approach for PCOS treatment.

scholarly journals Activation of the nuclear factor-κB pathway during postnatal lung inflammation preserves alveolarization by suppressing macrophage inflammatory protein-2

2015 ◽  
Vol 309 (6) ◽  
pp. L593-L604 ◽  
Author(s):  
Yanli Hou ◽  
Min Liu ◽  
Cristiana Husted ◽  
Chihhsin Chen ◽  
Kavitha Thiagarajan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Combined Treatment ◽  
Nuclear Factor Κb ◽  
Inflammatory Stress ◽  
Inflammatory Protein ◽  
Inflammatory Stimuli ◽  
Anti Inflammatory ◽  
Macrophage Inflammatory Protein

A significant portion of lung development is completed postnatally during alveolarization, rendering the immature lung vulnerable to inflammatory stimuli that can disrupt lung structure and function. Although the NF-κB pathway has well-recognized pro-inflammatory functions, novel anti-inflammatory and developmental roles for NF-κB have recently been described. Thus, to determine how NF-κB modulates alveolarization during inflammation, we exposed postnatal day 6 mice to vehicle (PBS), systemic lipopolysaccharide (LPS), or the combination of LPS and the global NF-κB pathway inhibitor BAY 11-7082 (LPS + BAY). LPS impaired alveolarization, decreased lung cell proliferation, and reduced epithelial growth factor expression. BAY exaggerated these detrimental effects of LPS, further suppressing proliferation and disrupting pulmonary angiogenesis, an essential component of alveolarization. The more severe pathology induced by LPS + BAY was associated with marked increases in lung and plasma levels of macrophage inflammatory protein-2 (MIP-2). Experiments using primary neonatal pulmonary endothelial cells (PEC) demonstrated that MIP-2 directly impaired neonatal PEC migration in vitro; and neutralization of MIP-2 in vivo preserved lung cell proliferation and pulmonary angiogenesis and prevented the more severe alveolar disruption induced by the combined treatment of LPS + BAY. Taken together, these studies demonstrate a key anti-inflammatory function of the NF-κB pathway in the early alveolar lung that functions to mitigate the detrimental effects of inflammation on pulmonary angiogenesis and alveolarization. Furthermore, these data suggest that neutralization of MIP-2 may represent a novel therapeutic target that could be beneficial in preserving lung growth in premature infants exposed to inflammatory stress.

scholarly journals Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rishi Man Chugh ◽  
Hang-soo Park ◽  
Abdeljabar El Andaloussi ◽  
Amro Elsharoud ◽  
Sahar Esfandyari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Therapeutic Option ◽  
Interleukin 10 ◽  
Reproductive Age ◽  
Mesenchymal Stem Cell Therapy ◽  
Anti Inflammatory

Abstract Background Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models. Methods For in vitro experiment, we treated conditioned media from BM-hMSC to androgen-producing H293R cells and analyzed androgen-producing gene expression. For in vivo experiment, BM-hMSC were implanted into letrozole (LTZ)-induced PCOS mouse model. BM-hMSC effect in androgen-producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot, animal tissue assay (H&E staining), and fertility by pup delivery. Results BM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improved in metabolic and reproductive markers in our PCOS model and able to restore fertility. Conclusion Our study demonstrates for the first time the efficacy of intra-ovarian injection of BM-hMSC or its secretome to treat PCOS-related phenotypes, including both metabolic and reproductive dysfunction. This approach may represent a novel therapeutic option for women with PCOS. Our results suggest that BM-hMSC can reverse PCOS-induced inflammation through IL-10 secretion. BM-hMSC might be a novel and robust therapeutic approach for PCOS treatment.

scholarly journals Physalin A Inhibits MAPK and NF-κB Signal Transduction Through Integrin αVβ3 and Exerts Chondroprotective Effect

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Lu ◽  
Xiaojun Yu ◽  
Shuang Liang ◽  
Peng Cheng ◽  
Zhenggang Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Integrin Αvβ3 ◽  
The Elderly ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Effects ◽  
Anti Inflammatory ◽  
Chondroprotective Effect

Osteoarthritis (OA) is a common articular ailment presented with cartilage loss and destruction that is common observed in the elderly population. Physalin A (PA), a natural bioactive withanolide, exerts anti-inflammatory residences in more than a few diseases; however, little is known about its efficacy for OA treatment. Here, we explored the therapeutic effects and potential mechanism of PA in mouse OA. After the in vitro administration of PA, the expression of inflammation indicators including inducible nitric oxide synthase and cyclooxygenase-2 was low, indicating that PA could alleviate the IL-1β-induced chondrocyte inflammation response. Moreover, PA reduced IL-1β-induced destruction of the extracellular matrix by upregulating the gene expression of anabolism factors, including collagen II, aggrecan, and sry-box transcription factor 9, and downregulating the gene expression of catabolic factors, including thrombospondin motif 5 and matrix metalloproteinases. In addition, the chondroprotective effect of PA was credited to the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, in vivo experiments showed that intra-articular injection of PA could alleviate cartilage destruction in a mouse OA model. However, the anti-inflammatory, anabolism enhancing, catabolism inhibiting, and MAPK and NF-κB signaling pathway inhibiting properties of PA on IL-1β-induced chondrocytes could be reversed when integrin αVβ3 is knocked down by siRNA. In conclusion, our work demonstrates that PA exhibits a chondroprotective effect that may be mediated by integrin αVβ3. Thus, PA or integrin αVβ3 might be a promising agent or molecular target for the treatment of OA.

scholarly journals Glucocorticoid-Induced Leucine Zipper-Mediated TLR2 Downregulation Accounts for Reduced Neutrophil Activity Following Acute DEX Treatment

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2228
Author(s):  
Erika Ricci ◽  
Elena Roselletti ◽  
Marco Gentili ◽  
Samuele Sabbatini ◽  
Stefano Perito ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Human Neutrophils ◽  
Wild Type ◽  
Tlr2 Expression ◽  
Glucocorticoid Treatment ◽  
Knock Out ◽  
Blood Neutrophils ◽  
Anti Inflammatory

Glucocorticoids are the most powerful anti-inflammatory and immunosuppressive pharmacological drugs available, despite their adverse effects. Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced gene that shares several anti-inflammatory properties with glucocorticoids. Although immunosuppressive effects of glucocorticoids on neutrophils remain poorly understood, we previously demonstrated that GILZ suppresses neutrophil activation under glucocorticoid treatment. Here, we sought to explore the regulation of Toll-like receptor 2 (TLR2) by the synthetic glucocorticoid dexamethasone (DEX) on neutrophils and the associated GILZ involvement. Peripheral blood neutrophils were isolated from wild type and GILZ-knock-out (KO) mice. TLR2 was found to be downregulated by the in vivo administration of glucocorticoids in wild type but not in GILZ-KO neutrophils, suggesting the involvement of GILZ in TLR2 downregulation. Accordingly, the TLR2-associated anti-fungal activity of neutrophils was reduced by DEX treatment in wild type but not GILZ-KO neutrophils. Furthermore, GILZ did not interact with NF-κB but was found to bind with STAT5, a pivotal factor in the regulation of TLR2 expression. A similar modulation of TLR2 expression, impaired phagocytosis, and killing activity was observed in circulating human neutrophils treated in vitro with DEX. These results demonstrate that glucocorticoids reduce the ability of neutrophils to respond to infections by downregulating TLR2 via GILZ, thereby reducing critical functions.

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 Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

2020 ◽  
Vol 21 (21) ◽  
pp. 7876
Author(s):  
Andrey V. Markov ◽  
Aleksandra V. Sen’kova ◽  
Valeriya O. Babich ◽  
Kirill V. Odarenko ◽  
Vadim A. Talyshev ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Nuclear Factor Κb ◽  
Raw264.7 Cells ◽  
Migration Activity ◽  
Akt Phosphorylation ◽  
Raw264.7 Macrophages ◽  
Anti Inflammatory ◽  
And Migration

Plant-extracted triterpenoids belong to a class of bioactive compounds with pleotropic functions, including antioxidant, anti-cancer, and anti-inflammatory effects. In this work, we investigated the anti-inflammatory and anti-oxidative activities of a semisynthetic derivative of 18βH-glycyrrhetinic acid (18βH-GA), soloxolone methyl (methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate, or SM) in vitro on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and in vivo in models of acute inflammation: LPS-induced endotoxemia and carrageenan-induced peritonitis. SM used at non-cytotoxic concentrations was found to attenuate the production of reactive oxygen species and nitric oxide (II) and increase the level of reduced glutathione production by LPS-stimulated RAW264.7 cells. Moreover, SM strongly suppressed the phagocytic and migration activity of activated macrophages. These effects were found to be associated with the stimulation of heme oxigenase-1 (HO-1) expression, as well as with the inhibition of nuclear factor-κB (NF-κB) and Akt phosphorylation. Surprisingly, it was found that SM significantly enhanced LPS-induced expression of the pro-inflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in RAW264.7 cells via activation of the c-Jun/Toll-like receptor 4 (TLR4) signaling axis. In vivo pre-exposure treatment with SM effectively inhibited the development of carrageenan-induced acute inflammation in the peritoneal cavity, but it did not improve LPS-induced inflammation in the endotoxemia model.

scholarly journals Effects of Berries on High-Fat Diet-Induced Inflammation

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 449-449
Author(s):  
Patricia Perez ◽  
Desiree Wanders ◽  
Hannah Land ◽  
Kathryn Chiang ◽  
Rami Najjar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Inflammatory Markers ◽  
In Vitro Study ◽  
Vitro Study ◽  
In Vivo Study ◽  
High Fat ◽  
Anti Inflammatory

Abstract Objectives Studies suggest that inflammation mediates the link between obesity and its comorbidities including type 2 diabetes and cardiovascular disease. Hence, there is a demand for effective alternative or complementary approaches to treat obesity-associated inflammation. The objective of this study was to determine whether consumption of blackberries (BL) and raspberries (RB) alone or in combination reduce obesity-induced inflammation. Methods In Vitro Study: RAW 264.7 macrophages were pretreated with either BL, RB, or BL + RB, each at a final concentration of 200 µg/mL for 2 h. LPS (1 ng/mL) was then added to the media for 16 h. mRNA expression of inflammatory cytokines was measured. In Vivo Study: Five-week-old mice were acclimated to a low-fat low-sucrose (LFLS) diet for one week after which mice were randomized 10 per group to one of five groups: 1) LFLS, 2) high-fat high-sucrose (HFHS), 3) HFHS + 10% BL, 4) HFHS + 10% RB, or 5) HFHS + 5% BL + 5% RB. Expression of inflammatory markers was measured in the liver as well as epididymal and inguinal white adipose tissue. Results In Vitro Study: Each berry alone and in combination suppressed the LPS-induced increase in inflammatory markers, with the combination (BL + RB) having the greatest effect. The combination suppressed LPS-induced expression of Ccl2, Tnfa, F4/80, and Il6 by 3.7−, 5.3−, 5.3−, and 4.4-fold, respectively. In Vivo Study: Gene expression analysis indicated that berry consumption had no significant effect on proinflammatory (Ccl2, Il1b, Tnfa, Il6, Itgam) or anti-inflammatory (Adipoq, Arg1, Mgl1) markers in adipose tissue depots or liver. However, relatively low gene expression of inflammatory markers in the tissues indicates that the mice fed the HFHS diet failed to develop a robust inflammatory state. Conclusions BL and RB have direct anti-inflammatory effects on immune cells. Initial analysis indicates that consumption of BL and RB has no significant effects on markers of inflammation in a diet-induced mouse model of obesity. However, it is possible that the relatively low levels of inflammation in these mice masked the anti-inflammatory potential of BL and RB. Ongoing analysis will provide additional insights into the effects of BL and RB on inflammation in these tissues. Funding Sources Lewis Foundation Award.

scholarly journals Effect of GCSB-5, a Herbal Formulation, on Monosodium Iodoacetate-Induced Osteoarthritis in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Joon-Ki Kim ◽  
Sang-Won Park ◽  
Jung-Woo Kang ◽  
Yu-Jin Kim ◽  
Sung Youl Lee ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Protein Expression ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Cartilage Explants ◽  
Therapeutic Effects ◽  
Monosodium Iodoacetate ◽  
Factor Α

Therapeutic effects of GCSB-5 on osteoarthritis were measured by the amount of glycosaminoglycan in rabbit articular cartilage explantsin vitro, in experimental osteoarthritis induced by intra-articular injection of monoiodoacetate in ratsin vivo. GCSB-5 was orally administered for 28 days.In vitro, GCSB-5 inhibited proteoglycan degradation. GCSB-5 significantly suppressed the histological changes in monoiodoacetate-induced osteoarthritis. Matrix metalloproteinase (MMP) activity, as well as, the levels of serum tumor necrosis factor-α, cyclooxygenase-2, inducible nitric oxide synthase protein, and mRNA expressions were attenuated by GCSB-5, whereas the level of interleukin-10 was potentiated. By GCSB-5, the level of nuclear factor-κB p65 protein expression was significantly attenuated but, on the other hand, the level of inhibitor of κB-α protein expression was increased. These results indicate that GCSB-5 is a potential therapeutic agent for the protection of articular cartilage against progression of osteoarthritis through inhibition of MMPs activity, inflammatory mediators, and NF-κB activation.

scholarly journals Early-Released Interleukin-10 Significantly Inhibits Lipopolysaccharide-Elicited Neuroinflammation In Vitro

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2173
Author(s):  
Yubao Wang ◽  
Pei Yu ◽  
Yi Li ◽  
Zhan Zhao ◽  
Xiaomei Wu ◽  
...  
Keyword(s):  
Late Phase ◽  
Interleukin 10 ◽  
Glial Cultures ◽  
Pilot Investigation ◽  
The Central Nervous System ◽  
Β2 Adrenergic Receptor ◽  
Anti Inflammatory ◽  
Protein Assays

Anti-inflammatory cytokine interleukin (IL)-10 is pivotal for limiting excessive inflammation in the central nervous system. Reports show that lipopolysaccharide (LPS)-induced microglial IL-10 emerges in a delayed manner in vitro and in vivo, lagging behind proinflammatory cytokines to facilitate the resolution of neuroinflammation. We hypothesized that IL-10 releases quite quickly based on our pilot investigation. Here, we uncovered a bimodal expression of microglial IL-10 gene transcription induced by LPS in mouse primary mixed glial cultures. This pattern consisted of a short brief early-phase and a long-lived late-phase, enabling the production of IL-10 protein in a rapid manner. The removal and addition of IL-10 protein assays indicated that early-released IL-10 exerted potent modulatory effects on neuroinflammation at picomolar levels, and IL-10 released at the onset of neuroinflammation is tightly controlled. We further showed that the early-released, but not the late-released, IL-10 was crucial for mediating and potentiating the anti-inflammatory function of a β2-adrenergic receptor agonist salmeterol. This study in vitro highlights the essential role of early-released IL-10 in regulating the appropriate degree of neuroinflammation, overturning the previous notion that microglial IL-10 produces and functions in a delayed manner and providing new insights into anti-inflammatory mechanisms-mediated neuroimmune homeostasis.

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