scholarly journals AB0058 CELL-TYPE SPECIFIC REGULATION OF IL-1R SIGNALING BY R835, A DUAL IRAK1/4 INHIBITOR

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1331.2-1331
Author(s):  
S. Braselmann ◽  
E. Tai ◽  
R. Frances ◽  
C. Young ◽  
V. Markovtsov ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kinase Activity ◽  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Dermal Fibroblasts ◽  
Lung Fibroblasts ◽  
Gm Csf ◽  
Nfkb Pathway ◽  
Low Levels

Background:Interleukin-1 beta (IL-1b) is a key mediator of the inflammatory response and is known to exacerbate damage during chronic disease and acute tissue injury. Through association with the adaptor protein Myd88, interleukin receptor associated kinases (IRAK)1 and 4 initiate signaling downstream of IL-1Rs resulting in the activation of the NFkB and MAPK pathways and the production of proinflammatory cytokines (1). IL-1Rs are broadly expressed across cell types and little is known about differences in signaling between cell types and the role of IRAK1 and IRAK4 kinase activity.Objectives:We have identified a potent and selective IRAK1/4 inhibitor, R835, that substantially suppressed the elevation of LPS (TLR4 agonist)-induced serum cytokines in healthy human volunteers in a recent phase 1 study. The aim of this study was to evaluate the effect of R835 on IL-1R signaling in primary human fibroblasts and endothelial cells.Methods:Human dermal fibroblasts, lung fibroblasts or endothelial cells were stimulated with IL-1b and the effect of R835 on the signaling pathway was evaluated by western blotting. Human dermal fibroblasts were stimulated with different amounts of IL-1b to evaluate both the signaling pathways activated and the cytokines produced. The ability of R835 to inhibit cytokine production induced by high or low amounts of IL-1b in dermal fibroblasts was assessed.Results:In human endothelial cells, inhibition of IRAK1/4 kinases with R835 resulted in a block of IL-1b-induced IRAK4 phosphorylation, IRAK1 degradation and downstream NFkB, p38 and JNK activation. In contrast, in both human primary dermal and lung fibroblasts stimulated with IL-1b, we observed potent inhibition of IRAK4 phosphorylation, IRAK1 degradation, and downstream JNK phosphorylation, but no inhibition of NFkB pathway proteins and only weak inhibition of p38. Upon titration of IL-1b we observed that dermal fibroblasts produced IL-8 and GRO in response to low levels of IL-1b (20pg/ml), and produced additional cytokines including G-CSF and GM-CSF with higher levels of IL-1b (400pg/ml). In the presence of low levels of IL-1b (20pg/ml), we observed a weak activation of NFkB pathway proteins and p38, compared to a very robust NFkB, p38 and additional JNK activation in the presence of higher levels of IL-1b (400pg/ml). Consistent with these results, in dermal fibroblasts, R835 showed little to no inhibition of IL-8 and GRO induced by low levels of IL-1b, but potently inhibited G-CSF and GM-CSF induced by high levels of IL-1b where JNK was activated.Conclusion:This study has elucidated signaling differences between cell types downstream of the IL-1R. In endothelial cells, as in myeloid cells, the kinase activity of IRAK1 and IRAK4 is required for the activation of all downstream signaling. Unexpectedly, in human fibroblasts, IRAK1/4 kinase activity appears to primarily regulate the JNK pathway, and not the NFkB pathway. Concomitant with that, only the cytokines induced by the additional activation of JNK in fibroblasts are regulated by a dual IRAK1/4 inhibitor. Clinically, an IRAK1/4 inhibitor may show select inhibition of IL-1b-induced cytokines depending on the tissue and cell type involved in inflammation.References:[1]Flannery S, Bowie A G. The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling. Biochemical Pharmacology, Volume 80, Issue 12, 15 December 2010, Pages 1981-1991.Disclosure of Interests:Sylvia Braselmann Shareholder of: Shareholder of Rigel Pharmaceuticals, Employee of: Employee of Rigel Pharmaceuticals, Ernest Tai Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Roy Frances Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Chi Young Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Vadim Markovtsov Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Esteban Masuda Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Vanessa Taylor Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals

scholarly journals Granulocyte-macrophage colony-stimulating factor expression by human fibroblasts is both upregulated and subsequently downregulated by interleukin-1

Blood ◽  
1995 ◽  
Vol 85 (1) ◽  
pp. 80-86 ◽  
Author(s):  
RR Patil ◽  
RF Borch
Keyword(s):  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Adenosine Monophosphate ◽  
Lung Fibroblasts ◽  
Mrna Levels ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Interleukin-1 (IL-1) treatment of human WI-38 lung fibroblasts results in granulocyte-macrophage colony-stimulating factor (GM-CSF) expression as well as a delayed increase in prostaglandin E2 (PGE2) production that closely correlates with the decline of GM-CSF mRNA levels. Pretreatment with PGE2 reduces the IL-1 induced GM-CSF mRNA and protein expression to 10% to 15% of control values at concentrations of PGE2 that are endogenously produced after IL-1 stimulation. Inhibition of PGE2 synthesis by indomethacin prolongs the IL-1 induced GM-CSF mRNA expression and increases the cumulative GM-CSF protein secretion. Exposure of WI-38 fibroblasts to PGE2 results in an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. The inhibition of GM-CSF expression by PGE2 can be mimicked by stable cAMP analogs as well as cAMP elevating agents such as cholera toxin, forskolin, and isobutylmethylxanthine. Thus the inhibition exerted by PGE2 is mediated via cAMP. Taken together, these results suggest that IL-1 stimulation of human fibroblasts provides not only the upregulatory signal for GM-CSF expression but also a delayed and indirect downregulatory signal that serves to limit GM-CSF expression in the continued presence of IL-1.

scholarly journals Interleukin-1, tumor necrosis factor, and the production of colony- stimulating factors by cultured mesenchymal cells

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1316-1323 ◽  
Author(s):  
CA Sieff ◽  
CM Niemeyer ◽  
SJ Mentzer ◽  
DV Faller
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Messenger Rna ◽  
Tumor Necrosis ◽  
Umbilical Vein ◽  
Interleukin 1 ◽  
Mesenchymal Cells ◽  
Colony Stimulating Factors ◽  
Gm Csf ◽  
Necrosis Factor

Abstract Although the genes for four hematopoietic colony-stimulating factors (CSFs) have been cloned, neither the mechanism of the regulation of their production nor their cellular origins have been established with certainty. Monocytes are known to produce colony-stimulating and burst- promoting activities, as well as several monokines such as interleukin- 1 (IL-1) and tumor necrosis factor (TNF). These monokines indirectly stimulate other mesenchymal cells to produce certain colony-stimulating factors such as granulocyte-macrophage CSF (GM-CSF). To determine whether monocytes produce other CSFs and if so, to compare the mechanism of regulation of production with that of endothelial cells and fibroblasts, we investigated the synthesis of CSFs by monocytes, human umbilical vein endothelial cells, and fibroblasts. We used total cellular RNA blot analysis to determine interleukin-3 (IL-3), GM-CSF, granulocyte CSF (G-CSF), and monocyte CSF (M-CSF) messenger RNA (mRNA) content and immunoprecipitation or bioassay to confirm the presence of the specific secreted proteins. The results indicate that M-CSF mRNA and protein are produced constitutively by all three cell types and their level of expression does not increase after induction. In contrast, GM-CSF and G-CSF mRNAs are barely detectable in uninduced monocytes and show an increase in expression after lipopolysaccharide treatment. Retrovirus-immortalized endothelial cells, unlike primary endothelial cells or both primary and immortalized fibroblasts, produce IL-1 constitutively; this correlates with their constitutive production of GM-CSF and G-CSF. IL-3 mRNA was not detectable in any of these cells either before or after induction. The results indicate that these mesenchymal cells can produce three CSFs: GM-CSF, G-CSF, and M-CSF; furthermore, the data suggest that the mechanism of regulation of M-CSF production is different from that of GM-CSF and G-CSF, and that the latter two inducible CSFs are regulated by different factors in monocytes compared with the other mesenchymal cells.

scholarly journals Erythroid burst-promoting activity produced by interleukin-1-stimulated endothelial cells is granulocyte-macrophage colony-stimulating factor

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1364-1367 ◽  
Author(s):  
GM Segal ◽  
E McCall ◽  
GC Jr Bagby
Keyword(s):  
Endothelial Cells ◽  
Mononuclear Cells ◽  
Umbilical Vein ◽  
Marrow Cell ◽  
Interleukin 1 ◽  
Colony Growth ◽  
Erythropoietic Activity ◽  
Gm Csf ◽  
Accessory Cells ◽  
Cells Cultured

Abstract Interleukin-1 (IL-1) induces cultured human umbilical vein endothelial cells to elaborate heterogeneous hematopoietic growth factors, including granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF and G-CSF, respectively). Because erythroid burst- promoting activity (BPA) is also elaborated by endothelial cells exposed to IL-1, we sought to determine whether the BPA released by IL- 1-induced endothelial cells simply reflects the known erythropoietic activity of GM-CSF or whether other uncharacterized factors might be involved. Media conditioned by multiply passaged endothelial cells cultured for three days with recombinant IL-1 alpha (ECMIL-1) stimulated erythroid burst and GM colony formation in cultures of human nonadherent T-lymphocyte-depleted marrow mononuclear cells. Pretreatment with an anti-GM-CSF antiserum neutralized all the BPA and 56% of the GM colony-stimulating activity (GM-CSA) in ECMIL-1. The antiserum used in these studies did not inhibit IL-3 or G-CSF activity and did not inhibit ECMIL-1-induced murine GM colony growth (a measure of human G-CSF). To examine whether GM-CSF induces BPA release by accessory cells, media conditioned by marrow cells cultured for three days with GM-CSF were tested in the colony growth assays. Pretreatment with anti-GM-CSF antiserum completely neutralized the BPA and GM-CSA of the marrow cell-conditioned medium. We conclude that GM-CSF is the BPA elaborated by IL-1-induced endothelial cells. The in vitro erythropoietic activity of GM-CSF is not dependent on induced BPA release by accessory cells and therefore likely results from a direct effect of GM-CSF on progenitor cells.

scholarly journals Vascular endothelial cells and granulopoiesis: interleukin-1 stimulates release of G-CSF and GM-CSF

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 99-103 ◽  
Author(s):  
KM Zsebo ◽  
VN Yuschenkoff ◽  
S Schiffer ◽  
D Chang ◽  
E McCall ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Interleukin 1 ◽  
Colony Growth ◽  
Mononuclear Phagocytes ◽  
Conditioned Media ◽  
Leukemic Cells ◽  
Gm Csf ◽  
Growth Assay

Abstract Cultured mononuclear phagocytes produce soluble factors that stimulate endothelial cells to release GM-colony-stimulating activity (GM-CSA). One such factor was recently identified as interleukin 1 (IL 1). Studies were designed to determine which types of granulopoietic factors are released by IL 1-stimulated endothelial cells. Supernatants from endothelial cells cultured for 3 days in medium containing IL 1 alpha and beta were tested in both murine and human CFU-GM colony growth assays. The effect of conditioned media on differentiation of WEHI-3B myelomonocytic leukemic cells was also examined. Control media containing IL 1 alone or unstimulated endothelial cell-conditioned media contained no detectable CSA in any bioassay. Medium conditioned by IL 1-stimulated endothelial cells stimulated the clonal growth of both human and murine CFU-GM and induced macrophage differentiation of WEHI-3B cells. Treatment of these conditioned media with a highly specific neutralizing monoclonal G-CSF antibody completely inhibited their activity in the murine CFU-GM assay, but only partially inhibited GM colony growth by human marrow. Treatment of the active conditioned media with a neutralizing rabbit anti-human GM-CSF antibody partially reduced the activity of the media in the human GM-colony growth assay. G-CSF radioimmunoassay of endothelial cell culture supernatants and Northern blot analysis of endothelial cell cytoplasmic RNA for GM-CSF gene transcripts confirmed that IL 1 induced expression of both G-CSF and GM-CSF genes. Because treatment of media with both antibodies abrogated all activity in the human GM colony growth assay, we conclude that IL 1-stimulated endothelial cells release both G and GM-CSF and that these are the only granulopoietic factors detectable in clonogenic assays released by these cells in vitro.

scholarly journals Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 1218-1221 ◽  
Author(s):  
JD Griffin ◽  
A Rambaldi ◽  
E Vellenga ◽  
DC Young ◽  
D Ostapovicz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stromal Cells ◽  
Interleukin 1 ◽  
Constitutive Expression ◽  
Conditioned Media ◽  
Acute Myeloblastic Leukemia ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

The interaction of acute myeloblastic leukemia (AML) cells with stromal cells was investigated by adding AML-conditioned media to cultures of human endothelial cells. This conditioned media contained factors that induced expression of both the granulocyte macrophage colony- stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) genes and release of colony stimulating activity from endothelial cells. The conditioned media contained interleukin-1 (IL-1) bioactivity and the endothelial cell stimulatory activity was partially neutralized by anti- IL-1 antiserum. Constitutive expression of the IL-1-beta gene was detected in ten of 17 AML cases analyzed. These results suggest that the unregulated secretion of IL-1 by AML cells can induce stromal cells in vitro to overproduce CSFs. This could contribute to the unrestricted growth of AML cells.

scholarly journals In vitro stimulatory effect of substance P on hematopoiesis

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 391-398
Author(s):  
P Rameshwar ◽  
D Ganea ◽  
P Gascon
Keyword(s):  
Endothelial Cells ◽  
Substance P ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Methyl Cellulose ◽  
Hematopoietic Growth Factors ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Macrophage Colony

The neuropeptide Substance P (SP) is widely distributed in the peripheral nervous system. Its biologic effects have been extensively studied in the immune system. However, even though the bone marrow (BM) is innervated with SP-immunoreactive fibers and some of its cells not only express SP receptors (T and B cells, endothelial cells, and macrophages) but also produce SP (macrophages, eosinophils, and endothelial cells), the effects of SP on hematopoiesis are scanty. Furthermore, SP induces the production of hematopoietic growth factors (HGFs) (interleukin-1 [IL-1], IL-6, and tumor necrosis factor alpha) from human monocytes. In this study, we have found a potent in vitro stimulatory effect of SP (10(-8) to 10(-12) mol/L) on hematopoiesis for both erythroid and granulocytic progenitors in short-term methyl- cellulose BM cultures. SP alone, in the absence of exogenous HGFs, is able to sustain hematopoiesis in vitro. This stimulatory effect of SP is: (1) mostly mediated by the adherent cells; (2) completely abrogated by two SP receptor (SP-R) antagonists; and (3) partially reduced by anti-IL-1, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Furthermore, it appears that the stimulatory effect of SP may be mediated by IL-3 and GM-CSF because we have also found that SP induces the release of these two cytokines from BM mononuclear cells. Considering that the SP effect occurs at concentrations as low as 10(-11) mol/L, and via a specific receptor, it appears that SP may play a physiologic role in regulating hematopoiesis, at least partially through the adherent BM cells and the release of HGFs, and may place SP, a neuropeptide, in a new category of hematopoietic regulators.

scholarly journals The Human Cytomegalovirus Ribonucleotide Reductase Homolog UL45 Is Dispensable for Growth in Endothelial Cells, as Determined by a BAC-Cloned Clinical Isolate of Human Cytomegalovirus with Preserved Wild-Type Characteristics

2002 ◽  
Vol 76 (18) ◽  
pp. 9551-9555 ◽  
Author(s):  
Gabriele Hahn ◽  
Hanna Khan ◽  
Fausto Baldanti ◽  
Ulrich H. Koszinowski ◽  
M. Grazia Revello ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Clinical Isolate ◽  
Human Cytomegalovirus ◽  
Ribonucleotide Reductase ◽  
Human Fibroblasts ◽  
Artificial Chromosome ◽  
Cell Types ◽  
Factor X ◽  
Wild Type ◽  
Human Endothelial Cells

ABSTRACT An endothelial cell-tropic and leukotropic human cytomegalovirus (HCMV) clinical isolate was cloned as a fusion-inducing factor X-bacterial artificial chromosome in Escherichia coli, and the ribonucleotide reductase homolog UL45 was deleted. Reconstituted virus RVFIX and RVΔUL45 grew equally well in human fibroblasts and human endothelial cells. Thus, UL45 is dispensable for growth of HCMV in both cell types.

scholarly journals Specific repression of granulocyte-macrophage and granulocyte colony- stimulating factor gene expression in interleukin-1-stimulated endothelial cells with antisense oligodeoxynucleotides

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 609-616 ◽  
Author(s):  
GM Segal ◽  
TD Smith ◽  
MC Heinrich ◽  
FS Ey ◽  
GC Bagby
Keyword(s):  
Endothelial Cells ◽  
Interleukin 1 ◽  
The Other ◽  
Antisense Oligodeoxynucleotides ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Translation Start ◽  
Antisense Odns ◽  
Stimulating Factor

Abstract Antisense oligodeoxynucleotides (ODNs) have been used to effect the specific inhibition of cellular gene expression. We have evaluated the application of this approach to the inhibition of interleukin-1 (IL-1)- induced granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) expression in cultured human umbilical vein endothelial cells. Antisense ODNs or control ODNs (sense ODNs or missense ODNs containing random base substitutions) were added to cultures of endothelial cells, the cells were induced with IL- 1 alpha, and the conditioned media were assayed for GM-CSF and G-CSF by quantitative bioassays and for immunoreactive GM-CSF by enzyme immunoassay. Antisense ODNs complementary to the first 15 or 18 bases of the translation start sites of GM-CSF or G-CSF mRNAs inhibited, in a concentration-dependent fashion, the IL-1-stimulated expression of the corresponding factor, but did not affect expression of the other factor. Control ODNs did not affect GM-CSF or G-CSF expression. Exposure to a GM-CSF antisense ODN, but not a control ODN, substantially reduced cytoplasmic GM-CSF mRNA levels in IL-1-stimulated endothelial cells. Neither ODN affected levels of endothelial leukocyte adhesion molecule (ELAM)1 or glyceraldehyde-3-phosphate dehydrogenase mRNAs. We conclude that antisense ODNs complementary to the translation start sites of GM-CSF or G-CSF mRNAs inhibit expression of the corresponding factor in a sequence-specific fashion and this effect is mediated, at least in part, by reduction in the cytoplasmic level of the targeted mRNA. Moreover, IL-1-induced GM-CSF or G-CSF expression does not depend on expression of the other factor.

scholarly journals Erythroid burst-promoting activity produced by interleukin-1-stimulated endothelial cells is granulocyte-macrophage colony-stimulating factor

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1364-1367 ◽  
Author(s):  
GM Segal ◽  
E McCall ◽  
GC Jr Bagby
Keyword(s):  
Endothelial Cells ◽  
Mononuclear Cells ◽  
Umbilical Vein ◽  
Marrow Cell ◽  
Interleukin 1 ◽  
Colony Growth ◽  
Erythropoietic Activity ◽  
Gm Csf ◽  
Accessory Cells ◽  
Cells Cultured

Interleukin-1 (IL-1) induces cultured human umbilical vein endothelial cells to elaborate heterogeneous hematopoietic growth factors, including granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF and G-CSF, respectively). Because erythroid burst- promoting activity (BPA) is also elaborated by endothelial cells exposed to IL-1, we sought to determine whether the BPA released by IL- 1-induced endothelial cells simply reflects the known erythropoietic activity of GM-CSF or whether other uncharacterized factors might be involved. Media conditioned by multiply passaged endothelial cells cultured for three days with recombinant IL-1 alpha (ECMIL-1) stimulated erythroid burst and GM colony formation in cultures of human nonadherent T-lymphocyte-depleted marrow mononuclear cells. Pretreatment with an anti-GM-CSF antiserum neutralized all the BPA and 56% of the GM colony-stimulating activity (GM-CSA) in ECMIL-1. The antiserum used in these studies did not inhibit IL-3 or G-CSF activity and did not inhibit ECMIL-1-induced murine GM colony growth (a measure of human G-CSF). To examine whether GM-CSF induces BPA release by accessory cells, media conditioned by marrow cells cultured for three days with GM-CSF were tested in the colony growth assays. Pretreatment with anti-GM-CSF antiserum completely neutralized the BPA and GM-CSA of the marrow cell-conditioned medium. We conclude that GM-CSF is the BPA elaborated by IL-1-induced endothelial cells. The in vitro erythropoietic activity of GM-CSF is not dependent on induced BPA release by accessory cells and therefore likely results from a direct effect of GM-CSF on progenitor cells.

scholarly journals Platelet effects on tissue factor and fibrinolytic inhibition of cultured human fibroblasts and vascular cells

Blood ◽  
1982 ◽  
Vol 60 (1) ◽  
pp. 140-147
Author(s):  
PE Smariga ◽  
JR Maynard
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Human Fibroblasts ◽  
Cellular Tissue ◽  
Cultured Human Fibroblasts ◽  
Platelet Concentration ◽  
The Media ◽  
Low Levels ◽  
Coagulation Pathway

Platelets stimulate tissue factor, the initiator of the extrinsic coagulation pathway, and increase fibrinolytic inhibition in fibroblasts grown in vitro. Cellular tissue factor increases an average of 2.8-fold over the control levels after a 6-hr incubation with platelets, and no activity is present in the media. Fibrinolytic inhibition is stimulated in both the fibroblasts and their media in the presence of platelets and accumulates throughout a 24-hr incubation. Neither leukocytes nor erythrocytes stimulate these changes. Both tissue factor and fibrinolytic inhibition increases are dependent on platelet concentration and are blocked by inhibitors of RNA or protein synthesis. Control smooth muscle cells have higher tissue factor and fibrinolytic inhibition than fibroblasts, but their response to the presence of platelets is similar. Confluent monolayers of endothelial cells have very low levels of tissue factor that are not altered by the presence of platelets. However, the ability of endothelial cells to inhibit fibrinolysis is enhanced by the presence of platelets. The fraction that stimulates tissue factor and fibrinolytic inhibition is distinct from platelet-derived growth factor and from the fraction that enhances leukocyte tissue factor. It is associated with an insoluble, nonmitogenic fraction that is not inactivated by phospholipase C, or diisopropylfluorophosphate, nor is it chloroform:methanol extractable. Platelets are a physiologic modulator for both cellular tissue factor and the fibrinolytic system in vitro.

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