A Combination of Geniposide and Chlorogenic Acid Combination Ameliorates Nonalcoholic Steatohepatitis in Mice by Inhibiting Kupffer Cell Activation

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide. Activation of Kupffer cells (KCs) is central to the development of diet-induced NASH. We investigated whether a combination of two active chemical components, geniposide and chlorogenic acid (GC), at a specific ratio (67 : 1), ameliorates diet-induced NASH and the underlying mechanisms involved. C57BL/6J mice exposed to a high-fat and high-cholesterol (HFHC) diet containing cholesterol, choline, and high-sugar drinking water, as well as RAW264.7 cells stimulated with lipopolysaccharide (LPS) were studied. The combination exerted a therapeutic effect on HFHC-induced NASH in mice. Simultaneously, GC was found to reduce the expression of cytokines secreted by hepatic macrophages, including tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, monocyte chemotactic protein 1 (MCP-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, GC reduced the number of KCs expressing F4/80. Furthermore, TNF-α, inducible nitric oxide synthase (INOS), IL-1β, and IL-6 mRNA and TNF-α protein expression levels were suppressed upon GC treatment in RAW264.7 cells. Our findings suggest that GC has a strong anti-inflammatory effect in NASH, and this effect can be attributed to the suppression of KC activity in the liver.

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Arrest of human dendritic cells at the CD34−/CD4+/HLA-DR+ stage in the bone marrow of NOD/SCID-human chimeric mice

Blood ◽

10.1182/blood.v97.11.3655 ◽

2001 ◽

Vol 97 (11) ◽

pp. 3655-3657 ◽

Cited By ~ 4

Author(s):

Masaharu Nobuyoshi ◽

Yoichiro Kusunoki ◽

Toshio Seyama ◽

Kazunori Kodama ◽

Akiro Kimura ◽

...

Keyword(s):

Bone Marrow ◽

Mononuclear Cells ◽

Chimeric Mice ◽

Human Cord Blood ◽

Gm Csf ◽

Hla Dr ◽

Tnf Α ◽

Macrophage Colony ◽

Factor Α ◽

Human Dendritic Cells

Human dendritic cell (DC) precursors were engrafted and maintained in NOD/SCID- human chimeric mice (NOD/SCID-hu mice) implanted with human cord blood mononuclear cells, although no mature human DCs were detected in lymphoid organs of the mice. Two months after implantation, bone marrow (BM) cells of NOD/SCID-hu mice formed colonies showing DC morphology and expressing CD1a in methylcellulose culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor α (TNF-α). The CD34−/CD4+/HLA-DR+ cell fraction in NOD/SCID-hu mouse BM generated CD1a+ cells that were highly stimulatory in mixed leukocyte reactions in culture with GM-CSF and TNF-α. These results suggest a strong potential for NOD/SCID-hu BM to generate human DCs, although DC differentiation may be blocked at the CD34−/CD4+/HLA-DR+ stage.

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Differential regulation of granulocyte-macrophage colony-stimulating factor mRNA and protein expression in human thyrocytes and thyroid-derived fibroblasts by interleukin-1α and tumour necrosis factor-α

Journal of Endocrinology ◽

10.1677/joe.0.1510277 ◽

1996 ◽

Vol 151 (2) ◽

pp. 277-285 ◽

Cited By ~ 6

Author(s):

G Aust ◽

A Hofmann ◽

S Laue ◽

S Ode-Hakim ◽

W A Scherbaum

Keyword(s):

Protein Expression ◽

Tumour Necrosis Factor Α ◽

Gm Csf ◽

Tnf Α ◽

Macrophage Colony Stimulating Factor ◽

Interleukin 1Α ◽

Macrophage Colony ◽

Factor Α ◽

Stimulating Factor ◽

Necrosis Factor

Abstract In this study, we provide the first report on the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by human thyroid epithelial cells. Primary cultures of highly purified thyrocytes and thyroid-derived fibroblasts (n=3) and three thyroid anaplastic and one largely papillary carcinoma cell lines were exposed to different potent GM-CSF stimulators, employing interleukin 1α (Il-1α) and tumour necrosis factor-α (TNF-α). Cytokine mRNA levels were monitored by semiquantitative reverse transcriptase-PCR including an internal heterologous competitor fragment after 3, 6 and 18 h of culture. Culture supernatants were assayed for GM-CSF using a highly sensitive ELISA (detection limit ≤ 0·5 pg/ml) after 24 h. Basal GM-CSF mRNA expression was higher in fibroblasts and SW 1736 cells compared with thyrocytes, C 634, 8505 C and HTh 74 cells. GM-CSF was spontaneously secreted by fibroblasts (means ± s.e.m.; 43 ± 15 pg/ml), SW 1736 (59 ± 4 pg/ml), HTh 74 (34 ± 4 pg/ml) and C 643 cells (12 ± 1 pg/ml) but not by thyrocytes and 8505 C cells. Treatment with Il-1α (10 U/ml) resulted in a marked increase of GM-CSF mRNA within 3 h and an increase or induction of protein expression in thyrocyte (2350 ± 214 pg/ml), fibroblast (5242 ± 1400 pg/ml), SW 1736 (20016 ± 280 pg/ml) and C 643 cultures (1285 ± 79 pg/ml). Stimulation with TNF-α (10 U/ml) yielded divergent results. No significant increase of GM-CSF mRNA or protein expression was found in thyrocytes although TNF-α receptor expression in these cells is well documented. Stimulation with TNF-α resulted in an increased GM-CSF production in fibroblasts (361 ± 14 pg/ml), HTh 74 (148 ± 51 pg/ml) and SW 1736 cultures (235 ± 43 pg/ml). TSH (10 mU/ml) did not stimulate GM-CSF secretion in thyrocytes and HTh 74 cells, both expressing the TSH receptor. Phorbol 12-myristate 13-acetate (10 ng/ml) enhanced GM-CSF mRNA and protein levels in all cell types investigated. Our data suggest that both thyrocytes and fibroblasts synthesize GM-CSF in response to Il-1α, but only fibroblasts respond to TNF-α with a significant increase in GM-CSF. Anaplastic thyroid carcinomas are potential GM-CSF producers. Journal of Endocrinology (1996) 151, 277–285

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Granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α in combination is a useful diagnostic biomarker to distinguish familial Mediterranean fever from sepsis

Arthritis Research & Therapy ◽

10.1186/s13075-021-02644-2 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Tomohiro Koga ◽

Kaori Furukawa ◽

Kiyoshi Migita ◽

Shimpei Morimoto ◽

Toshimasa Shimizu ◽

...

Keyword(s):

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Gm Csf ◽

Tnf Α ◽

Mediterranean Fever ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Factor Α ◽

Stimulating Factor ◽

Necrosis Factor

Abstract Objective To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis. Method We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis. Results Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%). Conclusion Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines.

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IL-10–producing macrophages preferentially clear early apoptotic cells

Blood ◽

10.1182/blood-2005-10-4144 ◽

2006 ◽

Vol 107 (12) ◽

pp. 4930-4937 ◽

Cited By ~ 147

Author(s):

Wei Xu ◽

Anja Roos ◽

Nicole Schlagwein ◽

Andrea M. Woltman ◽

Mohamed R. Daha ◽

...

Keyword(s):

Interleukin 10 ◽

Apoptotic Cells ◽

Gm Csf ◽

Inflammatory Status ◽

Tnf Α ◽

Macrophage Colony Stimulating Factor ◽

Anti Inflammatory ◽

Macrophage Colony ◽

Macrophage Subset ◽

Factor Α

AbstractEfficient clearance of apoptotic cells seems to be a prerequisite to prevent the development of autoimmunity. Here we identify that macrophage colony-stimulating factor (M-CSF)–driven macrophages (Mø2s) are potent phagocytes that have the unique capacity to preferentially bind and ingest early apoptotic cells. This macrophage subset has intrinsic anti-inflammatory properties, characterized by high interleukin-10 (IL-10) production in the absence of proinflammatory cytokines, such as IL-6 and tumor necrosis factor-α (TNF-α). Importantly, whereas the IL-6 and TNF-α production by granulocyte-macrophage (GM)–CSF–driven macrophages (Mø1s) is inhibited upon uptake of apoptotic cells, the anti-inflammatory status of Mø2 is retained during phagocytosis. Mø2s were shown to use CD14 to tether apoptotic cells, whereas recognition of phosphatidylserine (PS) contributed to uptake of early apoptotic cells. Mø2s showed more potent macropinocytosis compared with dendritic cells (DCs) and Mø1s, and uptake of apoptotic cells was inhibited by a macropinocytosis inhibitor. Our studies suggest that, under steady-state conditions, IL-10–producing Mø2s are prominently involved in the clearance of early apoptotic cells.

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Multiplexed Cytokine Protein Expression Profiles from Spreading Depression in Hippocampal Organotypic Cultures

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000126566.34753.30 ◽

2004 ◽

Vol 24 (8) ◽

pp. 829-839 ◽

Cited By ~ 36

Author(s):

Phillip E. Kunkler ◽

Raymond E. Hulse ◽

Richard P. Kraig

Keyword(s):

Time Course ◽

Spreading Depression ◽

Expression Profiles ◽

Interferon Γ ◽

Organotypic Cultures ◽

Gm Csf ◽

Tnf Α ◽

Macrophage Colony ◽

Factor Α ◽

Protein Expression Profiles

Cytokines are involved in ischemic tolerance, including that triggered by spreading depression (SD), yet their roles in neuroprotection remain incompletely defined. The latter may stem from the pleiotropic nature of these signaling molecules whose complexities for interaction might be better deciphered through simultaneous measurement of multiple targeted proteins. Accordingly, the authors used microsphere-based flow cytometric immunoassays and hippocampal organotypic cultures (HOTCs) to characterize the magnitude, time course, and diversity of cytokine (interleukin [IL] 1α, IL-1β, IL-2, IL-4, IL-6, IL-10, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon-γ [IFN-γ], and tumor necrosis factor-α [TNF-α]) response to SD. GM-CSF was not detected in HOTCs or media. However, SD triggered a significant, generalized increase in seven cytokines evident in HOTCs 6 hours later, with the remaining cytokine, IL-1β, becoming significantly different at 1 and 3 days. Additionally, these changes extended to include surrounding media for IL-6 and TNF-α by 1 and 3 days. This increase was localized to microglia via immunostaining for IL-1α, IL-1β, and interferon-γ. IL-10, although significantly more abundant in HOTCs 6 hours after SD, was significantly less abundant in surrounding media at that time and at 1 day. Finally, the generalized early increase in tissue cytokines later settled to a pattern at 3 days of recovery centering on changes in IL-1α, IL-1β, and TNF-α, cytokines capable of modulating ischemic injury.

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The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion

Blood ◽

10.1182/blood-2007-02-075366 ◽

2007 ◽

Vol 110 (9) ◽

pp. 3202-3208 ◽

Cited By ~ 59

Author(s):

Nayoung Kim ◽

Aurore Saudemont ◽

Louise Webb ◽

Montserrat Camps ◽

Thomas Ruckle ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Interferon Γ ◽

Cell Development ◽

Cytokine Secretion ◽

Gm Csf ◽

Relative Contribution ◽

Tnf Α ◽

Macrophage Colony ◽

Factor Α

Abstract The signal transduction pathways that lead activated natural killer (NK) cells to produce cytokines, releases cytotoxic granules, or do both, are not clearly dissected. For example, phosphoinositide 3-kinases (PI3Ks) are key players in the execution of both functions, but the relative contribution of each isoform is unknown. We show here that the catalytic isoform p110δ, not p110γ, was required for interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF) secretion, whereas neither was necessary for cytotoxicity. Yet, when both p110δ and p110γ isoforms were inactivated by a combination of genetic and biochemical approaches, cytotoxicity was decreased. NK-cell numbers were also affected by the lack of p110δ but not p110γ and more severely so in mice lacking both subunits. These results provide genetic evidence that p110δ is the dominant PI3K isoform for cytokine secretion by NK cells and suggest that PI3Ks cooperate during NK-cell development and cytotoxicity.

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Are interleukin-16 and thrombopoietin new tools for the in vitro generation of dendritic cells?

Blood ◽

10.1182/blood-2004-03-0885 ◽

2004 ◽

Vol 104 (13) ◽

pp. 4020-4028 ◽

Cited By ~ 31

Author(s):

Silvia Della Bella ◽

Stefania Nicola ◽

Inna Timofeeva ◽

Maria Luisa Villa ◽

Armando Santoro ◽

...

Keyword(s):

T Cells ◽

Surface Expression ◽

Gm Csf ◽

Human Cd34 ◽

Tnf Α ◽

Macrophage Colony ◽

Factor Α ◽

Inhibitory Molecules ◽

Tolerogenic Dcs

Abstract The effects of interleukin 16 (IL-16) on dendritic cell (DC) generation from human CD34+ progenitor cells are not known. Here, we show that IL-16 added to a basal cocktail comprised of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, Flt-3 ligand (Flt3L), and tumor necrosis factor α (TNF-α) does induce the CD34+ hematopoietic cells to proliferate in vitro and to differentiate into phenotypically and functionally mature DCs. IL-16 exerts this function more efficiently than stem cell factor (SCF) as a control, thrombopoietin (TPO), or IL-16 plus TPO. Moreover, we show that the combination of IL-16 plus TPO induces the generation of tolerogenic DCs, able to induce an anergic state in T cells that persists when T cells are rechallenged with immunogenic DCs. An altered pattern of cytokine production, a reduced expression of the C-type lectin DC-SIGN, and an increased surface expression of the inhibitory molecules immunoglobulin-like transcript 2 (ILT-2), ILT-3, and ILT-4 may all contribute to confer the tolerogenic properties of these DCs. Generation of tolerogenic DCs may aid the exploration of new therapeutic strategies to promote tolerance to autoantigens and prevent disease development. (Blood. 2004;104:4020-4028)

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Anti-Inflammatory Effects of Phlebia sp. Extract in Lipopolysaccharide-stimulated RAW 264.7 Macrophages

10.20944/preprints202112.0361.v1 ◽

2021 ◽

Author(s):

Eui Hyeon Lim ◽

Seul-Ki Mun ◽

Jong-Jin Kim ◽

Dong-Jo Chang ◽

Sung-Tae Yee

Keyword(s):

Tissue Damage ◽

Biological Activities ◽

Raw 264.7 ◽

Raw 264.7 Macrophages ◽

Gm Csf ◽

Tnf Α ◽

Macrophage Colony Stimulating Factor ◽

Anti Inflammatory ◽

Macrophage Colony ◽

Factor Α

Lichens are a life form in which algae and fungi have a symbiotic relationship. A lichen has various biological activities, including anti-inflammatory and anti-proliferative activities. Inflammation is a response caused by various factors, such as infection by pathogens or tissue damage; excessive reactions can contribute to the etiology of chronic diseases, such as asthma, brain damage, and serious tissue damage. This study demonstrates the anti-inflammatory effect of ethyl acetate extract from Phlebia sp. on NF-κB and AP-1 pathways in the lipopolysaccharide-treated RAW 264.7 cell. Especially, Phlebia sp. extract inhibits the phosphorylation of AP-1 signaling (c-Fos and c-Jun) and its upstream MKK/MAPKs (MKK4, MKK7 and JNK), which induced a decrease in the production of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in downstream of AP-1 signaling. Furthermore, Phlebia sp. extract inhibited the production of final inflammatory effector molecules involved in AP-1 signaling, including nitric oxide (NO) and prostaglandin E2 (PGE2). Here, we report that Phlebia sp. extract has the potential to be developed as an anti-inflammatory agent.

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Anti-Inflammatory Effect of Simonsinol on Lipopolysaccharide Stimulated RAW264.7 Cells through Inactivation of NF-κB Signaling Pathway

Molecules ◽

10.3390/molecules25163573 ◽

2020 ◽

Vol 25 (16) ◽

pp. 3573

Author(s):

Lian-Chun Li ◽

Zheng-Hong Pan ◽

De-Sheng Ning ◽

Yu-Xia Fu

Keyword(s):

Nitric Oxide ◽

Signaling Pathway ◽

Morphological Changes ◽

Raw264.7 Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Tnf Α ◽

Anti Inflammatory ◽

Factor Α ◽

Oxide Synthase ◽

Necrosis Factor

Simonsinol is a natural sesqui-neolignan firstly isolated from the bark of Illicium simonsii. In this study, the anti-inflammatory activity of simonsinol was investigated with a lipopolysaccharide (LPS)-stimulated murine macrophages RAW264.7 cells model. The results demonstrated that simonsinol could antagonize the effect of LPS on morphological changes of RAW264.7 cells, and decrease the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 cells, as determined by Griess assay and enzyme-linked immunosorbent assay (ELISA). Furthermore, simonsinol could downregulate transcription of inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 as measured by reverse transcription polymerase chain reaction (RT-PCR), and inhibit phosphorylation of the alpha inhibitor of NF-κB (IκBα) as assayed by Western blot. In conclusion, these data demonstrate that simonsinol could inhibit inflammation response in LPS-stimulated RAW264.7 cells through the inactivation of the nuclear transcription factor kappa-B (NF-κB) signaling pathway.

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Granulocyte-Macrophage Colony-Stimulating Factor-Deficient Mice Have Impaired Resistance to Blood-Stage Malaria

Infection and Immunity ◽

10.1128/iai.69.1.129-136.2001 ◽

2001 ◽

Vol 69 (1) ◽

pp. 129-136 ◽

Cited By ~ 49

Author(s):

Julie Riopel ◽

MiFong Tam ◽

Karkada Mohan ◽

Michael W. Marino ◽

Mary M. Stevenson

Keyword(s):

Blood Stage ◽

Colony Stimulating Factor ◽

Necrosis Factor Alpha ◽

Gm Csf ◽

Tnf Α ◽

Macrophage Colony Stimulating Factor ◽

Ifn Γ ◽

Macrophage Colony ◽

Stimulating Factor ◽

Blood Stage Malaria

ABSTRACT The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudiAS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-γ) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-γ levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-α) levels were significantly increased in KO mice and were significantly higher than TNF-α levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-γ and TNF-α production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.

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