IFN-γ–mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3274-3282 ◽  
Author(s):  
Annabel F. Valledor ◽  
Luís Arpa ◽  
Ester Sánchez-Tilló ◽  
Mònica Comalada ◽  
Cristina Casals ◽  
...  
Keyword(s):  
Growth Factors ◽  
Time Course ◽  
Growth Arrest ◽  
Inhibition Of Proliferation ◽  
Antiproliferative Effects ◽  
Mapk Activity ◽  
Ifn Γ ◽  
Mapk Phosphatase ◽  
Macrophage Colony ◽  
Erk Activity

Abstract Macrophages have the capacity to proliferate in response to specific growth factors, such as macrophage-colony stimulating factor (M-CSF). In the presence of several cytokines and activating factors, macrophages undergo growth arrest, become activated, and participate in the development of an immune response. We have previously observed that activation of extracellularly regulated kinase 1/2 (ERK-1/2) is required for macrophage proliferation in response to growth factors. A short and early pattern of ERK activity correlated with the proliferative response. In contrast, slightly prolonged patterns of activity of these kinases were induced by signals that lead to macrophage activation and growth arrest. IFN-γ is the main endogenous Th1-type macrophage activator. Here we report that stimulation with IFN-γ prolongs the pattern of ERK activity induced by M-CSF in macrophages. These effects correlate with IFN-γ–mediated inhibition of the expression of several members of the MAPK phosphatase family, namely MKP-1, -2, and -4. Moreover, inhibition of MKP-1 expression using siRNA technology or synthetic inhibitors also led to elongated ERK activity and significant blockage of M-CSF–dependent proliferation. These data suggest that subtle changes in the time course of activity of members of the MAPK family contribute to the antiproliferative effects of IFN-γ in macrophages.

scholarly journals Peptide growth factors stimulate macrophage colony-stimulating factor in murine stromal cells

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 103-109 ◽  
Author(s):  
SL Abboud ◽  
M Pinzani
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Growth Factor ◽  
Stromal Cells ◽  
Time Course ◽  
Tnf Alpha ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Bone marrow stromal cells influence hematopoiesis through cell-cell interaction and release of hematopoietic growth factors. Macrophage colony-stimulating factor (M-CSF) is constitutively produced by several murine and human stromal cell lines and is induced by inflammatory mediators such as interleukin-1 alpha or tumor necrosis factor-alpha (TNF-alpha) in a variety of mesenchymal cells. Other potentially important regulatory molecules such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), released by activated monocytes in response to inflammation, stimulate the growth of human stromal cells. However, the effect of these peptide mitogens on M-CSF expression in stromal cells has not been explored. In this study, we used TC-1 murine bone marrow-derived stromal cells that constitutively secrete M-CSF to determine the effect of PDGF and bFGF on cell proliferation and M-CSF gene expression. PDGF and bFGF, but not TNF- alpha, were potent mitogens for the TC-1 cells. Similar to mouse L cells, TC-1 murine stromal cells constitutively expressed two major mRNA transcripts of 4.4 and 2.2 kb that hybridized to a murine M-CSF cDNA. PDGF, bFGF, and TNF-alpha markedly stimulated the steady-state expression of M-CSF mRNA with different time-course kinetics. The increased expression of M-CSF mRNA was associated with enhanced secretion of M-CSF as determined by radioimmunoassay. These findings suggest that PDGF, bFGF, and TNF-alpha may regulate hematopoiesis indirectly through release of M-CSF by stromal cells and may modulate, at least in part, the hematopoietic response to inflammation.

scholarly journals Peptide growth factors stimulate macrophage colony-stimulating factor in murine stromal cells

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 103-109 ◽  
Author(s):  
SL Abboud ◽  
M Pinzani
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Growth Factor ◽  
Stromal Cells ◽  
Time Course ◽  
Tnf Alpha ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Bone marrow stromal cells influence hematopoiesis through cell-cell interaction and release of hematopoietic growth factors. Macrophage colony-stimulating factor (M-CSF) is constitutively produced by several murine and human stromal cell lines and is induced by inflammatory mediators such as interleukin-1 alpha or tumor necrosis factor-alpha (TNF-alpha) in a variety of mesenchymal cells. Other potentially important regulatory molecules such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), released by activated monocytes in response to inflammation, stimulate the growth of human stromal cells. However, the effect of these peptide mitogens on M-CSF expression in stromal cells has not been explored. In this study, we used TC-1 murine bone marrow-derived stromal cells that constitutively secrete M-CSF to determine the effect of PDGF and bFGF on cell proliferation and M-CSF gene expression. PDGF and bFGF, but not TNF- alpha, were potent mitogens for the TC-1 cells. Similar to mouse L cells, TC-1 murine stromal cells constitutively expressed two major mRNA transcripts of 4.4 and 2.2 kb that hybridized to a murine M-CSF cDNA. PDGF, bFGF, and TNF-alpha markedly stimulated the steady-state expression of M-CSF mRNA with different time-course kinetics. The increased expression of M-CSF mRNA was associated with enhanced secretion of M-CSF as determined by radioimmunoassay. These findings suggest that PDGF, bFGF, and TNF-alpha may regulate hematopoiesis indirectly through release of M-CSF by stromal cells and may modulate, at least in part, the hematopoietic response to inflammation.

Decorin inhibits macrophage colony-stimulating factor proliferation of macrophages and enhances cell survival through induction of p27Kip1 and p21Waf1

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2124-2133 ◽  
Author(s):  
Jordi Xaus ◽  
Mònica Comalada ◽  
Marina Cardó ◽  
Annabel F. Valledor ◽  
Antonio Celada
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Cell Survival ◽  
Interferon Γ ◽  
Colony Stimulating Factor ◽  
Inhibition Of Proliferation ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Erk Activity ◽  
Stimulating Factor

Decorin is a small proteoglycan that is ubiquitous in the extracellular matrix of mammalian tissues. It has been extensively demonstrated that decorin inhibits tumor cell growth; however, no data have been reported on the effects of decorin in normal cells. Using nontransformed macrophages from bone marrow, results of this study showed that decorin inhibits macrophage colony-stimulating factor (M-CSF)–dependent proliferation by inducing blockage at the G1 phase of the cell cycle without affecting cell viability. In addition, decorin rescues macrophages from the induction of apoptosis after growth factor withdrawal. Decorin induces the expression of the cdk inhibitors p21Waf1 and p27Kip1. Using macrophages from mice where these genes have been disrupted, inhibition of proliferation mediated by decorin is related to p27Kip1 expression, whereas p21Waf1expression is necessary to protect macrophages from apoptosis. Decorin also inhibits M-CSF–dependent expression of MKP-1 and extends the kinetics of ERK activity, which is characteristic when macrophages become activated instead of proliferating. The effect of decorin on macrophages is not due to its interaction with epidermal growth factor or interferon-γ receptors. Furthermore, decorin increases macrophage adhesion to the extracellular matrix, and this may be partially responsible for the expression of p27Kip1 and the modification of ERK activity, but not for the increased cell survival.

Targeting Platelets Containing Electro-encapsulated lloprost to Balloon Injured Aorta in Rats

1995 ◽  
Vol 73 (03) ◽  
pp. 535-542 ◽  
Author(s):  
N Crawford ◽  
A Chajara ◽  
G Pfliegler ◽  
B EI Gamal ◽  
L Brewer ◽  
...  
Keyword(s):  
Time Course ◽  
Therapeutic Potential ◽  
Simple Procedure ◽  
Rat Aorta ◽  
Balloon Injury ◽  
Post Injury ◽  
Antiproliferative Effects ◽  
Platelet Deposition ◽  
Total Dna ◽  
Novel Drug

SummaryDrugs can be electro-encapsulated within platelets and targeted to damaged blood vessels by exploiting the platelet’s natural haemostatic properties to adhere to collagen and other vessel wall constituents revealed by injury. A rat aorta balloon angioplasty model has been used to study the effect on platelet deposition of giving iloprost loaded platelets i.v. during the balloon injury. After labelling the circulating platelets with 111-Indium before balloon injury, time course studies showed maximum platelet deposition on the injured aorta occurred at about 1 h post-injury and the deposition remained stable over the next 2-3 h. When iloprost-loaded platelets were given i.v. during injury and the circulating platelet pool labelled with 111-Indium 30 min later, platelet deposition, measured at 2 h postinjury, was substantially and significantly reduced compared with control platelet treatment. Some antiproliferative effects of iloprost-loaded platelets given i.v. during injury have also been observed. Whereas the incorporation of [3H]-thymidine into aorta intima-media DNA at 3 days post injury was 62-fold higher in balloon injured rats than in control sham operated rats, thymidine incorporation into intima/media of rats which had received iloprost loaded platelets during injury was reduced as compared with rats subjected only to the injury procedure. The reduction was only of near significance, however, but at 14 days after injury the total DNA content of the aorta intima/media of rats given iloprost loaded platelets during injury was significantly reduced. Although iloprost loaded platelets can clearly inhibit excessive platelet deposition, other encapsulated agents may have greater anti-proliferative effects. These studies have shown that drug loaded platelets can be targeted to injured arteries, where they may be retained as depots for local release. We believe this novel drug delivery protocol may have therapeutic potential in reducing the incidence of occlusion and restenosis after angioplasty and thrombolysis treatment. Electro-encapsulation of drugs into platelets is a simple procedure and, using autologous and fully biocompatible and biodegradable platelets as delivery vehicles, might overcome some of the immunological and toxicological problems which have been encountered with other delivery vectors such as liposomes, microbeads, synthetic microcapsules and antibodies.

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

2001 ◽  
Vol 69 (1) ◽  
pp. 129-136 ◽  
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.

Heparin stimulates the proliferation of intestinal epithelial cells in primary culture

1994 ◽  
Vol 107 (2) ◽  
pp. 401-411
Author(s):  
N. Flint ◽  
F.L. Cove ◽  
G.S. Evans
Keyword(s):  
Growth Factors ◽  
Heparan Sulphate ◽  
Primary Cultures ◽  
Cell Types ◽  
Heparin Binding ◽  
Epithelial Proliferation ◽  
Inhibition Of Proliferation ◽  
Trophic Effect ◽  
Heparin Binding Growth Factors

Heparin is a sulphated glycosaminoglycan derived from mast cells and has a number of functions including the inhibition of proliferation in several cell types and interactions with a range of heparin-binding growth factors. We report that heparin is a trophic factor in primary cultures of rat small intestinal epithelium. Heparin elicits a dose-dependent increase in epithelial proliferation and inhibits the growth of associated mesenchyme. The trophic effect of this molecule is not reproduced by other glycosaminoglycans including heparan sulphate but is dependent upon extensive molecular sulphation. Highly sulphated polysaccharides that are structurally unrelated to heparin (e.g. dextran sulphate and pentosan polysulphate) also stimulate epithelial proliferation in primary cultures. Heparin may act by the potentiation of mesenchyme-derived heparin-binding growth factors and these data suggest an in vivo role for mast cell-derived heparin in mucosal wound regeneration.

scholarly journals Confluence of Vascular Endothelial Cells Induces Cell Cycle Exit by Inhibiting p42/p44 Mitogen-Activated Protein Kinase Activity

1999 ◽  
Vol 19 (4) ◽  
pp. 2763-2772 ◽  
Author(s):  
Francesc Viñals ◽  
Jacques Pouysségur
Keyword(s):  
Cell Cycle ◽  
Endothelial Cells ◽  
Growth Factors ◽  
Vascular Endothelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Vascular Endothelial ◽  
Cell Cycle Exit ◽  
Mapk Activation ◽  
Mapk Activity ◽  
Mitogen Activated Protein

ABSTRACT Like other cellular models, endothelial cells in cultures stop growing when they reach confluence, even in the presence of growth factors. In this work, we have studied the effect of cellular contact on the activation of p42/p44 mitogen-activated protein kinase (MAPK) by growth factors in mouse vascular endothelial cells. p42/p44 MAPK activation by fetal calf serum or fibroblast growth factor was restrained in confluent cells in comparison with the activity found in sparse cells. Consequently, the induction of c-fos, MAPK phosphatases 1 and 2 (MKP1/2), and cyclin D1 was also restrained in confluent cells. In contrast, the activation of Ras and MEK-1, two upstream activators of the p42/p44 MAPK cascade, was not impaired when cells attained confluence. Sodium orthovanadate, but not okadaic acid, restored p42/p44 MAPK activity in confluent cells. Moreover, lysates from confluent 1G11 cells more effectively inactivated a dually phosphorylated active p42 MAPK than lysates from sparse cells. These results, together with the fact that vanadate-sensitive phosphatase activity was higher in confluent cells, suggest that phosphatases play a role in the down-regulation of p42/p44 MAPK activity. Enforced long-term activation of p42/p44 MAPK by expression of the chimera ΔRaf-1:ER, which activates the p42/p44 MAPK cascade at the level of Raf, enhanced the expression of MKP1/2 and cyclin D1 and, more importantly, restored the reentry of confluent cells into the cell cycle. Therefore, inhibition of p42/p44 MAPK activation by cell-cell contact is a critical step initiating cell cycle exit in vascular endothelial cells.

scholarly journals The Effect of JAK Inhibitor on the Survival, Anagen Re-Entry, and Hair Follicle Immune Privilege Restoration in Human Dermal Papilla Cells

2020 ◽  
Vol 21 (14) ◽  
pp. 5137
Author(s):  
Jung Eun Kim ◽  
Yu Jin Lee ◽  
Hye Ree Park ◽  
Dong Geon Lee ◽  
Kwan Ho Jeong ◽  
...  
Keyword(s):  
Growth Factors ◽  
Hair Follicle ◽  
Dermal Papilla ◽  
Immune Privilege ◽  
Jak Inhibitors ◽  
Dermal Papilla Cells ◽  
Ifn Γ ◽  
Vitro Model ◽  
Stat Pathway

Topical or systemic administration of JAK inhibitors has been shown to be a new treatment modality for severe alopecia areata (AA). Some patients show a good response to JAK inhibitors, but frequently relapse after cessation of the treatment. There have been no guidelines about the indications and use of JAK inhibitors in treating AA. The basic pathomechanism of AA and the relevant role of JAK inhibitors should support how to efficiently use JAK inhibitors. We sought to investigate the effect of JAK1/2 inhibitor on an in vitro model of AA and to examine the possible mechanisms. We used interferon gamma-pretreated human dermal papilla cells (hDPCs) as an in vitro model of AA. Ruxolitinib was administered to the hDPCs, and cell viability was assessed. The change of expression of the Wnt/β-catenin pathway, molecules related to the JAK-STAT pathway, and growth factors in ruxolitinib-treated hDPCs was also examined by reverse transcription PCR and Western blot assay. We examined immune-privilege-related molecules by immunohistochemistry in hair-follicle culture models. Ruxolitinib did not affect the cell viability of the hDPCs. Ruxolitinib activated several molecules in the Wnt/β-catenin signaling pathway, including Lef1 and β-catenin, and suppressed the transcription of DKK1 in hDPCs, but not its translation. Ruxolitinib reverted IFN-γ-induced expression of caspase-1, IL-1β, IL-15, and IL-18, and stimulated several growth factors, such as FGF7. Ruxolitinib suppressed the phosphorylation of JAK1, JAK2 and JAK3, and STAT1 and 3 compared to IFN-γ pretreated hDPCs. Ruxolitinib pretreatment showed a protective effect on IFN-γ-induced expression of MHC-class II molecules in cultured hair follicles. In conclusion, ruxolitinib modulated and reverted the interferon-induced inflammatory changes by blocking the JAK-STAT pathway in hDPCs under an AA-like environment. Ruxolitinib directly stimulated anagen-re-entry signals in hDPCs by affecting the Wnt/β-catenin pathway and promoting growth factors in hDPCs. Ruxolitinib treatment prevented IFN-γ-induced collapse of hair-follicle immune privilege.

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