Alarmin S100A9 Induces Proinflammatory and Catabolic Effects Predominantly in the M1 Macrophages of Human Osteoarthritic Synovium

2016 ◽  
Vol 43 (10) ◽  
pp. 1874-1884 ◽  
Author(s):  
Martijn H. van den Bosch ◽  
Arjen B. Blom ◽  
Rik F. Schelbergen ◽  
Marije I. Koenders ◽  
Fons A. van de Loo ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Proinflammatory Cytokines ◽  
Colony Stimulating Factor ◽  
Canonical Wnt Signaling ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Canonical Wnt ◽  
Stimulating Factor ◽  
Stimulation Of

Objective.The alarmins S100A8 and S100A9 have been shown to regulate synovial activation, cartilage damage, and osteophyte formation in osteoarthritis (OA). Here we investigated the effect of S100A9 on the production of proinflammatory cytokines and matrix metalloprotease (MMP) in OA synovium, granulocyte macrophage colony-stimulating factor (GM-CSF)-differentiated/macrophage colony-stimulating factor (M-CSF)-differentiated macrophages, and OA fibroblasts.Methods.We determined which cell types in the synovium produced S100A8 and S100A9. Further, the production of proinflammatory cytokines and MMP, and the activation of canonical Wnt signaling, was determined in human OA synovium, OA fibroblasts, and monocyte-derived macrophages following stimulation with S100A9.Results.We observed that S100A8 and S100A9 were mainly produced by GM-CSF–differentiated macrophages present in the synovium, and to a lesser extent by M-CSF–differentiated macrophages, but not by fibroblasts. S100A9 stimulation of OA synovial tissue increased the production of the proinflammatory cytokines interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor-α. Additionally, various MMP were upregulated after S100A9 stimulation. Experiments to determine which cell type was responsible for these effects revealed that mainly stimulation of GM-CSF–differentiated macrophages and to a lesser extent M-CSF-differentiated macrophages with S100A9 increased the expression of these proinflammatory cytokines and MMP. In contrast, stimulation of fibroblasts with S100A9 did not affect their expression. Finally, stimulation of GM-CSF–differentiated, but not M-CSF–differentiated macrophages with S100A9 activated canonical Wnt signaling, whereas incubation of OA synovium with the S100A9 inhibitor paquinimod reduced the activation of canonical Wnt signaling.Conclusion.Predominantly mediated by M1-like macrophages, the alarmin S100A9 stimulates the production of proinflammatory and catabolic mediators and activates canonical Wnt signaling in OA synovium.

Effect of inclusion of serum and granulocyte - macrophage colony stimulating factor on secretion of interferon-τ during the in vitro culture of ovine embryos

2005 ◽  
Vol 17 (5) ◽  
pp. 513 ◽  
Author(s):  
John Rooke ◽  
Morag Ewen ◽  
Tom McEvoy ◽  
Gary Entrican ◽  
Cheryl Ashworth
Keyword(s):  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Individual Culture ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Oviductal Fluid ◽  
Stimulating Factor ◽  
Stimulation Of ◽  
Plot Design

In each of three experiments, in vitro-matured and -fertilised zygotes were cultured to Day 7 post insemination in synthetic oviductal fluid (SOF). In Experiment 1, zygotes were cultured in groups in either SOF plus albumin (SOFA) or serum (SOFS) and then blastocysts were cultured individually for a further 24 h without a change of media. In Experiment 2, zygotes were cultured in groups using a 2 × 2 factorial design in SOFA or SOFS, with or without recombinant ovine granulocyte–macrophage colony stimulating factor (GM-CSF; 5 ng mL−1). Blastocysts were then cultured individually using a split-plot design in SOFA or SOFS with or without GM-CSF. In Experiment 3, zygotes were cultured in SOFA in which GM-CSF was absent (A) or present (P) during Days 1–3, Days 3–5 or Days 5–7 of IVC in six combinations as follows: AAA, AAP, APP, PPP, PPA and PAA. Serum or GM-CSF increased secretion of interferon (IFN)-τ in Experiments 1 and 2 both between Days 5 and 7 of group culture and during individual culture. Secretion of IFN-τ during individual culture was determined by the medium in which embryos were group cultured and the effects of GM-CSF and serum were not additive. In Experiment 3, the presence of GM-CSF between Days 1 and 3 of culture was responsible for stimulation of secretion of IFN-τ between Days 5 and 7; IFN-τ secretion was detected as early as Day 3 post insemination.

scholarly journals Stimulation of human myelopoiesis by leukotrienes B4 and C4: interactions with granulocyte-macrophage colony-stimulating factor

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 352-356
Author(s):  
L Stenke ◽  
M Mansour ◽  
P Reizenstein ◽  
JA Lindgren
Keyword(s):  
Colony Formation ◽  
Bone Marrow Cells ◽  
Growth Stimulation ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Synthase Inhibitor ◽  
Stimulating Factor ◽  
Stimulation Of

The regulatory role of leukotrienes (LT) on human myelopoiesis was investigated. Mononuclear bone marrow cells from 31 healthy donors were cultivated in the presence of suboptimal concentrations of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for 10 days in semisolid agar. The addition of LTC4 or LTB4 to the cultures dose- dependently stimulated myeloid stem cell proliferation. Maximal effects were observed at 10(-8) mol/L, at which LTC4 induced a 91% +/- 23% (mean +/- SEM; P = .004) and LTB4 a 73% +/- 22% (P = .008) increase in colony formation. In contrast, addition of the LTB4 isomer 5(S), 12(S)- diHETE did not affect the growth. LTD4 exerted a weak potentiating effect on progenitor proliferation (17% +/- 7% growth stimulation at 10(-10) mol/L; P = .034), whereas LTE4 was without consistent effect. Furthermore, LTC4-induced stimulation of colony formation was insensitive to the LTD4 antagonist ICI 198615. The dual lipoxygenase and prostaglandin endoperoxide synthase inhibitor CL42A potently suppressed the proliferation of myeloid colonies, a suppression that could be reversed by parallel addition of LTB4 or LTC4. The results suggest that both LTB4 and LTC4 possess strong and specific synergistic stimulatory effects on GM-CSF-induced human myeloid progenitor cell growth.

scholarly journals Clinical and cytogenetic responses to granulocyte-macrophage colony- stimulating factor in therapy-related myelodysplasia

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2463-2470
Author(s):  
WJ Gradishar ◽  
MM Le Beau ◽  
R O'Laughlin ◽  
JW Vardiman ◽  
RA Larson
Keyword(s):  
Neutrophil Count ◽  
Effective Control ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Transfusion Requirements ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Initial Starting ◽  
Stimulating Factor ◽  
Stimulation Of

We treated 10 patients with a therapy-related myelodysplastic syndrome with escalating doses of granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) in a phase II trial and used sequential cytogenetic analyses to determine whether there was stimulation of nonclonal hematopoiesis. The GM-CSF was administered by continuous intravenous infusion over 2 hours daily for 14 days, followed by a 14- day rest period. The initial starting dose was 60 micrograms/m2/d. The GM-CSF dose was escalated within individual patients to 125 micrograms/m2, 250 micrograms/m2, and then 500 micrograms/m2/d until the peripheral blood neutrophil count at least doubled and exceeded 1,000/microL. GM-CSF treatment then continued in monthly maintenance cycles. During 57 treatment courses, the neutrophil count increased in 52 but only doubled and exceeded 1,000/microL in 21. Mild eosinophilia was stimulated in five patients, but only two had greater than 1,000 eosinophils/microL. In only three patients was any stimulation of platelet or red blood cell production observed, and thus, little change in transfusion requirements occurred. The bone marrow karyotypes from individual patients either remained completely abnormal or became increasingly abnormal over the course of treatment. We found no evidence that GM-CSF preferentially stimulated normal marrow stem cells to proliferate or had the ability to eradicate the cytogenetically abnormal clone by inducing terminal differentiation. Although the effect on granulopoiesis was transient and dependent on continued GM- CSF treatment, the increase in the neutrophil count was clinically important in some patients, allowing more effective control of ongoing infections.

Bcl-3 Expression and Nuclear Translocation Are Induced by Granulocyte-Macrophage Colony-Stimulating Factor and Erythropoietin in Proliferating Human Erythroid Precursors

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1225-1234 ◽  
Author(s):  
Min-Ying Zhang ◽  
Edward W. Harhaj ◽  
Laurie Bell ◽  
Shao-Cong Sun ◽  
Barbara A. Miller
Keyword(s):  
Nuclear Translocation ◽  
Mrna Levels ◽  
Colony Stimulating Factor ◽  
Reporter Plasmid ◽  
Gm Csf ◽  
Erythroid Precursors ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Stimulation Of

Bcl-3 is a proto-oncogene involved in the chromosomal translocation t(14;19) found in some patients with chronic lymphocytic leukemia. It shares structural similarities with and is a member of the IκB family of proteins. In this report, involvement of Bcl-3in hematopoietic growth factor-stimulated erythroid proliferation and differentiation was examined. In TF-1 cells, an erythroleukemia cell line, granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo) greatly enhanced Bcl-3 expression at both the protein and mRNA levels in association with stimulation of proliferation. Bcl-3 protein was also highly expressed in early burst-forming unit-erythroid (BFU-E)–derived erythroid precursors (day 7) and decreased during maturation (days 10 and 14), suggesting that Bcl-3 is involved in normal erythroid proliferation. In these hematopoietic cells, Bcl-3 was hyperphosphorylated. GM-CSF and Epo modulated the subcellular localization of Bcl-3. Upon stimulation of TF-1 cells with GM-CSF or Epo, the nuclear translocation ofBcl-3 was dramatically enhanced. Overexpression of Bcl-3 in TF-1 cells by transient transfection along with the NF-κB factors p50 or p52 resulted in significant induction of an human immunodeficiency virus–type 1 (HIV-1) κB-TATA-luceriferase reporter plasmid, demonstrating that Bcl-3 has a positive role in transactivation of κB-containing genes in erythroid cells. Stimulation with GM-CSF enhanced c-myb mRNA expression in these cells. Bcl-3 in nuclear extracts of TF-1 cells bound to a κB enhancer in the c-mybpromoter together with NF-κB2/p52 and this binding activity was enhanced by GM-CSF stimulation. Furthermore, cotransfection of Bcl-3 with p52 or p50 in TF-1 cells resulted in significant activation of ac-myb κB-TATA-luceriferase reporter plasmid. These findings suggest that Bcl-3 may participate in the transcriptional regulation of certain κB-containing genes involved in hematopoiesis, includingc-myb. © 1998 by The American Society of Hematology.

scholarly journals Stimulation of human myelopoiesis by leukotrienes B4 and C4: interactions with granulocyte-macrophage colony-stimulating factor

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 352-356 ◽  
Author(s):  
L Stenke ◽  
M Mansour ◽  
P Reizenstein ◽  
JA Lindgren
Keyword(s):  
Colony Formation ◽  
Bone Marrow Cells ◽  
Growth Stimulation ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Synthase Inhibitor ◽  
Stimulating Factor ◽  
Stimulation Of

Abstract The regulatory role of leukotrienes (LT) on human myelopoiesis was investigated. Mononuclear bone marrow cells from 31 healthy donors were cultivated in the presence of suboptimal concentrations of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for 10 days in semisolid agar. The addition of LTC4 or LTB4 to the cultures dose- dependently stimulated myeloid stem cell proliferation. Maximal effects were observed at 10(-8) mol/L, at which LTC4 induced a 91% +/- 23% (mean +/- SEM; P = .004) and LTB4 a 73% +/- 22% (P = .008) increase in colony formation. In contrast, addition of the LTB4 isomer 5(S), 12(S)- diHETE did not affect the growth. LTD4 exerted a weak potentiating effect on progenitor proliferation (17% +/- 7% growth stimulation at 10(-10) mol/L; P = .034), whereas LTE4 was without consistent effect. Furthermore, LTC4-induced stimulation of colony formation was insensitive to the LTD4 antagonist ICI 198615. The dual lipoxygenase and prostaglandin endoperoxide synthase inhibitor CL42A potently suppressed the proliferation of myeloid colonies, a suppression that could be reversed by parallel addition of LTB4 or LTC4. The results suggest that both LTB4 and LTC4 possess strong and specific synergistic stimulatory effects on GM-CSF-induced human myeloid progenitor cell growth.

scholarly journals Granulocyte-macrophage colony-stimulating factor enhances selective effector functions of tissue-derived macrophages

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 573-578
Author(s):  
DL Coleman ◽  
JA Chodakewitz ◽  
AH Bartiss ◽  
JW Mellors
Keyword(s):  
Peritoneal Macrophages ◽  
Colony Stimulating Factor ◽  
Murine Peritoneal Macrophage ◽  
Effector Functions ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Stimulation Of

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by a variety of cells at sites of exposure to antigens. GM-CSF has a stimulatory effect on a number of neutrophil functions, but the effect on macrophage function is less clear. We investigated the effect of purified murine recombinant GM-CSF on murine peritoneal macrophage oxidative metabolism, Fc-dependent phagocytosis, anti-Toxoplasma activity, and expression of class II major histocompatibility antigen (Iad). GM-CSF significantly increased phorbol myristate acetate- and zymosan-elicited H2O2 release by resident and thioglycollate-elicited macrophages after 48 hours in vitro. The effect of recombinant GM-CSF was blocked by polyclonal anti-GM-CSF antibody and was not altered by lipopolysaccharide (0.01 to 1.0 microgram/mL). GM-CSF also stimulated Fc-dependent phagocytosis by peritoneal macrophages, although the stimulation of resident macrophages (1.4-fold) was less dramatic than that of thioglycollate-elicited cells (2.1-fold). GM-CSF (at doses up to 100 U/mL) had no effect on macrophage anti-Toxoplasma activity or on expression of Iad. In addition to stimulating macrophage growth, GM-CSF selectively promotes the functional capacity of tissue-derived macrophages.

scholarly journals Regulation of c-myc expression by granulocyte-macrophage colony- stimulating factor in human leukemia cells

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2716-2723
Author(s):  
EL Schwartz ◽  
H Chamberlin ◽  
AB Brechbuhl
Keyword(s):  
Leukemia Cells ◽  
Population Doubling ◽  
Colony Stimulating Factor ◽  
Biochemical Basis ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Camp Levels ◽  
Stimulating Factor ◽  
Stimulation Of

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates both the proliferation and functional properties of normal and leukemic myeloid cells via cell surface receptors. The postreceptor mechanisms for these two actions, and the extent to which they represent overlapping biochemical pathways, have not been fully clarified. We have examined the actions of GM-CSF on the expression of c-myc, an early response oncogene associated with the proliferative stimulus of growth factors. GM-CSF reduced the population doubling time of HL-60 leukemia cells from 32 hours to 25 hours, and, at concentrations that were correlated with mitogenicity, induced a rapid twofold increase in the level of c-myc mRNA. Nuclear runoff studies indicated that GM-CSF approximately doubled the transcription rate of c-myc by reversing the transcription attenuation that occurs at the exon 1-intron 1 junction. GM-CSF had no effect on the half-life of c-myc messenger RNA. The biochemical basis for the modulation of c-myc expression by GM-CSF was explored. GM-CSF treatment caused intracellular alkalinization of the cells as measured using the fluorescent probe 2′, 7-bis (2- carboxyethyl)-5(and-6) carboxyfluorescein (BCECF). The sodium channel blocker amiloride prevented the GM-CSF-induced change in pH, but did not affect the stimulation of c-myc transcription by GM-CSF. Agents that increase cellular cyclic adenosine monophosphate (cAMP) levels (prostaglandin E2 and cholera toxin) blocked the actions of GM-CSF on c- myc; however, these agents also reduced the basal level of c-myc expression. GM-CSF caused a rapid (5 minutes) and transient decline in cellular cyclic guanosine monophosphate (cGMP) levels, and a slower (30 minutes) and transient decrease in cellular cAMP levels. These observations are consistent with the hypothesis that the declines in cAMP and cGMP are associated with a stimulation of HL-60 proliferation, while previously reported manipulations that elevate cyclic nucleotides are related to an inhibition of HL-60 proliferation and the potentiation of differentiation.

scholarly journals Granulocyte-macrophage colony-stimulating factor enhances selective effector functions of tissue-derived macrophages

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 573-578 ◽  
Author(s):  
DL Coleman ◽  
JA Chodakewitz ◽  
AH Bartiss ◽  
JW Mellors
Keyword(s):  
Peritoneal Macrophages ◽  
Colony Stimulating Factor ◽  
Murine Peritoneal Macrophage ◽  
Effector Functions ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Stimulation Of

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is produced by a variety of cells at sites of exposure to antigens. GM-CSF has a stimulatory effect on a number of neutrophil functions, but the effect on macrophage function is less clear. We investigated the effect of purified murine recombinant GM-CSF on murine peritoneal macrophage oxidative metabolism, Fc-dependent phagocytosis, anti-Toxoplasma activity, and expression of class II major histocompatibility antigen (Iad). GM-CSF significantly increased phorbol myristate acetate- and zymosan-elicited H2O2 release by resident and thioglycollate-elicited macrophages after 48 hours in vitro. The effect of recombinant GM-CSF was blocked by polyclonal anti-GM-CSF antibody and was not altered by lipopolysaccharide (0.01 to 1.0 microgram/mL). GM-CSF also stimulated Fc-dependent phagocytosis by peritoneal macrophages, although the stimulation of resident macrophages (1.4-fold) was less dramatic than that of thioglycollate-elicited cells (2.1-fold). GM-CSF (at doses up to 100 U/mL) had no effect on macrophage anti-Toxoplasma activity or on expression of Iad. In addition to stimulating macrophage growth, GM-CSF selectively promotes the functional capacity of tissue-derived macrophages.

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