Changes in blood macrophage colony-stimulating factor levels after cesarean section in normotensive pregnancy and preeclampsia

BACKGROUND: Macrophage colony-stimulating factor (M-CSF) stimulates the proliferation and differentiation of placental trophoblasts and may regulate trophoblast invasion into the placental bed. M-CSF levels in peripheral blood show a significant increase in preeclampsia. Thus, the present study examined changes in blood levels of M-CSF before and after cesarean section and compared them between normotensive and preeclamptic pregnant women. METHODS: Peripheral blood was collected before, 1 day after, and 10 days after cesarean section from 27 women, 12 of whom were preeclamptic pregnant patients with a mean blood pressure of 162/98 mm Hg and 15 were age- and gestational age-matched normotensive pregnant women (normotensive control subjects). Peripheral blood was also collected once from 15 age-matched healthy, normal cycling women (nonpregnant control subjects). M-CSF level was determined by the sandwich enzyme-linked immunosorbent assay (ELISA) method using 3 antibodies. RESULTS: In normotensive and preeclamptic pregnancies, the M-CSF levels increased significantly (P < 0.01) 1 day after surgery but then decreased significantly (P < 0.01) at 10 days after surgery. Before and 1 day after surgery, the M-CSF levels were significantly higher (P < 0.01) in preeclamptic patients than in normotensive control subjects, but not at 10 days after surgery. CONCLUSIONS: The blood M-CSF levels were significantly higher in preeclampsia than in normotensive pregnancies, before cesarean section. The M-CSF levels in the circulation at 1 day after surgery increased significantly. The increase was about 270 U/mL net and at similar levels in 2 groups. Thus, increases in M-CSF levels after cesarean section may occur via similar mechanisms in normotensive and preeclamptic pregnancies. The M-CSF level in normotensive pregnancies and preeclampsia decreased and returned to the normal level at 10 days after cesarean section.     

Increased macrophage colony-stimulating factor levels in immune thrombocytopenic purpura

Thrombocytopenia is a dose-limiting toxicity of macrophage colony- stimulating factor (M-CSF) in preclinical and initial phase I trials. Modulation of macrophage-mediated platelet destruction in immune thrombocytopenic purpura (ITP) may be affected by M-CSF activity. In this study, plasma levels of M-CSF were determined by a sensitive radioimmunoassay in 23 patients with ITP. These were compared with control levels measured in 24 healthy subjects. M-CSF levels were significantly higher in the ITP patients than in the control subjects (218 v 179, P < .02); however, there was a great deal of overlap. The highest M-CSF levels (median = 299 U/mL) were observed in three patients with Evan's syndrome. Patients with severe ITP (platelets < 25,000/microL) had intermediate M-CSF levels (median = 231 U/mL) and those with mild thrombocytopenia (> 25,000/microL) had normal levels (median = 173 U/mL). Sixteen patients were treated with corticosteroids: 10 responded and 6 did not. Median M-CSF levels were higher in those who failed to respond compared with responders (272 v 202, P < .05). These findings suggest M-CSF may influence macrophage- mediated platelet destruction in ITP.     

Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels

Recombinant human macrophage colony-stimulating factor (rhM-CSF) is a hematopoietic growth factor that stimulates the growth, differentiation, proliferation, and activation of cells of the monocyte/macrophage lineage. rhM-CSF was administered to rabbits and nonhuman primates to evaluate effects on cholesterol homeostasis. Decreases in plasma cholesterol concentrations were observed during rhM-CSF administration. The observed mean (+/- SD) decreases over a range of doses in nonhuman primates receiving rhM-CSF by continuous intravenous infusion (CIVI) or intravenous bolus (IVB) injection were approximately 16% +/- 8% and 43% +/- 10%, respectively. Low-density lipoprotein (LDL) cholesterol levels decreased 55% +/- 9% from pretreatment baseline values in the animals receiving rhM-CSF by IVB. Normocholesterolemic New Zealand white rabbits receiving rhM-CSF over a range of doses by CIVI showed a decrease from baseline in total cholesterol of approximately 28% +/- 17%, with LDL cholesterol levels decreasing by approximately 72% +/- 33%, while high-density lipoprotein levels showed variable changes, including increased values. A decrease of 36% +/- 26% in total plasma cholesterol was observed in Watanabe Heritable Hyperlipidemic rabbits receiving rhM-CSF by CIVI for 7 days. This decrease was attributable almost entirely to decreases in LDL cholesterol, which fell approximately 34% +/- 24% from baseline. Although the mechanism of this cholesterol-lowering effect is unknown, these results strongly suggest that rhM-CSF may provide a novel treatment for hypercholesterolemia and may be useful in investigations into the mechanisms of cholesterol homeostasis and atherogenesis.     

High serum human macrophage colony-stimulating factor level during pregnancy.

Using a specific enzyme immunoassay, we monitored the serum levels of human macrophage colony-stimulating factor (hM-CSF) in pregnant women during gestation and after delivery. During pregnancy there was a marked elevation of maternal serum hM-CSF level, which returned to the baseline level within 3 weeks after delivery. The changes in maternal serum hM-CSF level were associated with changes in the numbers of monocytes and neutrophils in the maternal peripheral blood. Fetal sera prepared from cord blood samples also had a high hM-CSF level. In contrast to the baseline level of hM-CSF in maternal sera after delivery, the hM-CSF levels of newborn infants at 1 to 7 days after birth were higher than fetal levels, indicating that fetuses and newborn infants are a source of hM-CSF. The serum hM-CSF levels of infants at 22 to 35 days were between fetal levels and normal adult levels. Human M-CSF found in the serum of pregnant women and in cord blood was predominantly the large form of M-CSF, with a molecular mass of 85 kDa. Human M-CSF levels in amniotic fluid at 30 to 40 weeks were higher than those in cord blood sera at the same stage, indicating that the uterus is another source of hM-CSF. The roles played by hM-CSF during pregnancy need to be investigated.     

Fluctuations in plasma macrophage colony-stimulating factor levels during autologous peripheral blood stem cell transplantation for haematologic diseases

Plasma macrophage colony-stimulating factor (M-CSF) levels were measured in 13 haematologic patients treated with autologous peripheral blood stem cell transplantation (PBSCT). Six of the patients showed an increase in M-CSF peak levels (>3000 pg/ml) during the conditioning and stem cell infusion period. The peak levels of M-CSF in this phase correlated with thrombomodulin levels, indicating the endothelial origin of plasma M-CSF. However, the M-CSF levels were not influenced by TNFalpha. More patients with high M-CSF levels (>5000 pg/ml) suffered from organ failure than those with lower M-CSF levels. These results suggest that high M-CSF levels may correlate with cellular or organ damage in patients treated with PBSCT.     

Detection of endogenous macrophage colony-stimulating factor (M-CSF) in human blood

We have detected endogenous human macrophage colony-stimulating factor (M-CSF) in blood of normal individuals, using a novel RIA that accurately measures M-CSF concentrations as low as 60 U/ml (1.2 ng/ml) in the presence of serum proteins. The RIA uses an antibody to highly purified recombinant human M-CSF and is calibrated to a mouse bone marrow colony-forming assay. Ten samples of normal human blood plasma contained an average 118 +/- 9 U/ml of M-CSF, and similar concentrations were detected in serum prepared from the same individuals. RIA-positive samples contained biologically active M-CSF, as determined in a colony assay performed on mouse bone marrow cells. The M-CSF biological activity was removed by specific immune precipitation and inhibited by addition of M-CSF antibody. Physical characterization of plasma M-CSF was done by immunoblotting after partial purification on controlled pore glass and immunoaffinity chromatography. The major reduced protein species of plasma M-CSF had an apparent molecular weight of about 24 kd, and minor species of 30, 45, and 60-70 kd were also present. The RIA results on ten normal individuals suggest that endogenous circulating M-CSF is present at a low but detectable concentration. This RIA can be used to measure M-CSF in clinical samples that contain serum proteins and other growth factors that may interfere with accurate bioassay determinations.     

Peritoneal fluid and plasma levels of human macrophage colony-stimulating factor in relation to peritoneal fluid macrophage content

The peritoneal fluid (PF) of women with infertility (especially in the presence of endometriosis) contains increased numbers of leukocytes, 90% to 95% of which are macrophages. The high numbers of peritoneal macrophages presumably result from an influx of blood monocytes into the peritoneum, and/or from local proliferation of peritoneal macrophages. Once in the peritoneal cavity, monocytes differentiate into tissue macrophages. Mononuclear phagocyte proliferation and differentiation are influenced by different cytokines, including macrophage colony-stimulating factor (M-CSF). The purpose of this study was to determine the relationship of M-CSF levels in human PF and plasma to the macrophage content, and to the patient diagnoses. Mean concentrations of PF M-CSF were higher than plasma levels (2.44 +/- 0.13 v 0.95 +/- 0.06 ng/mL, respectively). The mean concentrations of plasma M-CSF did not differ in samples from women of different diagnostic groups (normal, peritoneal adhesions, endometriosis, inactive pelvic inflammatory disease, uterine fibroids, and idiopathic infertility), but the PF concentration was slightly higher in normal women. The absolute (total) amount of PF M-CSF in normal women was lower than in those of the other diagnostic groups. The total amount of PF M-CSF in all women correlated closely with the total number of peritoneal macrophages. The tubal patency status (open versus closed) did not influence the plasma and PF concentrations of M-CSF, nor the PF absolute amount of M-CSF. The PF M-CSF may have come from peritoneal macrophages, fibroblasts, mesothelial cells, or endothelial cells. PF M-CSF may play important roles in the proliferation and/or the differentiation of peritoneal mononuclear phagocytes.     

Granulocyte/macrophage colony-stimulating factor stimulates monocyte and tissue macrophage proliferation and enhances their responsiveness to macrophage colony-stimulating factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a specific humoral growth factor that stimulates both neutrophilic granulocyte and macrophage production by bone marrow hematopoietic progenitor cells. GM- CSF also stimulates the proliferation and clonal growth of both tissue macrophages and blood monocytes. Although at low concentrations GM-CSF was unable to support the long-term growth of tissue macrophages, it greatly enhanced their responsiveness to macrophage CSF (M-CSF, or CSF- 1). This effect was also observed by treating macrophages with GM-CSF for a short time. GM-CSF did not compete with M-CSF for binding to M- CSF receptors nor was it inactivated by treatment with anti-M-CSF antiserum. Treatment of tissue macrophages with GM-CSF led to a rapid but transient downregulation of M-CSF receptors; prolonged incubation at 37 degrees C, however, resulted in a restoration and upregulation of M-CSF receptors. Identical effects were observed with both native or recombinant GM-CSF. This study suggests that GM-CSF regulates tissue macrophage production by two modes of action: (a) direct stimulation of macrophage proliferation, and (b) enhancement of their responsiveness to M-CSF.     

Human macrophage colony-stimulating factor levels are elevated in pregnancy and in immune thrombocytopenia.

Plasma macrophage colony-stimulating factor (M-CSF) levels were measured by enzyme immunosorbent assay (ELISA) using horse and rabbit polyvalent antibodies raised against human M-CSF purified from urine (hM-CSF). Plasma M-CSF levels in nonpregnant female controls were 364 +/- 69 U/mL (mean +/- SD, n = 20). Pregnancy results in significant elevation of circulating M-CSF levels (541 +/- 164 U/mL, n = 46, P < .0005). M-CSF levels were increased by 28 weeks' gestation and did not increase further in later pregnancy. M-CSF levels were also measured in 20 female controls before and after commencing on the oral contraceptive pill. There was no effect of the contraceptive pill on plasma M-CSF levels (364 +/- 69 U/mL before v 373 +/- 66 U/mL after commencing on the pill). In 28 nonpregnant patients with untreated immune thrombocytopenic purpura, (ITP), plasma M-CSF levels were significantly increased (797 +/- 402 U/mL, n = 28, v 364 +/- 69 U/mL in controls, N = 20, P < .0005). Pregnant ITP patients had higher levels of plasma M-CSF (929 +/- 327 U/mL, n = 25) than nonpregnant patients, but this difference was not significant. Elevated levels of M-CSF in ITP may reflect activation of the reticuloendothelial system (RES), which could result in positive feedback to increase the destruction of platelets. The increase in M-CSF associated with pregnancy could contribute to the exacerbation of latent ITP in pregnancy.     

Circulating levels of granulocyte macrophage colony-stimulating factor in patients with the systemic inflammatory response syndrome

OBJECTIVES: Granulocyte-macrophage colony stimulating factor (GM-CSF) is a key regulator cytokine that modulates the proliferation and maturation of polymorphonuclear and mononuclear progenitors. This study was designed to investigate and clarify the role of GM-CSF in 52 critically ill patients with systemic inflammatory response syndrome (SIRS). METHODS: Serum levels of GM-CSF were detected by an immunoenzyme assay. RESULTS: Our results clearly show that the serum concentrations of GM-CSF were significantly elevated in patients with infectious and noninfectious SIRS (33.2+/-45.7pg/ml, controls: 17.2+/-9.8pg/ml; p=0.0303). In addition, GM-CSF levels significantly decreased in patients with SIRS, particularly in patients with infectious SIRS, 5 and 7 days later. There was a clear tendency toward higher levels of GM-CSF in patients with poor, as compared with those having a good outcome of the disease. CONCLUSION: These results show that GM-CSF may play an important role in patients with infectious and noninfectious SIRS, and that GM-CSF levels progressively and significantly decrease in patients with infectious SIRS.     

Elevated levels of serum macrophage colony-stimulating factor in normotensive pregnancies complicated by intrauterine fetal growth restriction

OBJECTIVE: Macrophage colony-stimulating factor (M-CSF) is considered an essential cytokine for placental growth and maintenance. M-CSF also may regulate trophoblast invasion into the placental bed. The aim of the present study was to evaluate whether serum M-CSF levels were altered in normotensive pregnancies complicated by intrauterine growth restriction (IUGR) arising from unknown factors. Plasma thrombin-antithrombin complex (TAT) levels and the pulsatility index (PI) values also were measured. PATIENTS AND METHODS: This study enrolled 47 Japanese women experiencing normotensive pregnancies with single fetuses. Of these pregnancies, 20 were complicated by IUGR arising from unknown factors; these women later delivered small-for-gestational-age (SGA) infants. The other 27 women later delivered appropriate-for-gestational-age infants (controls). The women's ages and gestational ages did not differ significantly between the two groups. Maternal peripheral blood was collected, and the levels of serum M-CSF and plasma TAT were compared between two groups. The M-CSF level was determined by the sandwich enzyme-linked immunosorbent assay method and the TAT level by the enzyme immunoassay method. The PI value for the middle cerebral artery of the fetuses was calculated. RESULTS: Serum levels of M-CSF were significantly higher (p < 0.005) in pregnancies complicated by IUGR that produced SGA infants than in controls. Plasma levels of TAT also were significantly higher (p < 0.02) in pregnancies that produced SGA infants than in controls. The PI values were significantly lower (p < 0.05) in pregnancies that produced SGA infants than in controls. CONCLUSIONS: This study demonstrated significant increases in serum M-CSF levels in women with normotensive pregnancies complicated by IUGR arising from unknown factors who later delivered SGA infants. To the best of our knowledge, this is the first such report. Elevated serum M-CSF levels may be related to placental hypoxia leading to pregnancies complicated by IUGR.     

Effects of histologic type on levels of macrophage colony-stimulating factor in liquid contents of benign ovarian tumors

BACKGROUND: Normal ovarian tissue is rich in cytokines. Cytokines are important in the physiology of ovarian function. Most of the same cytokines that are found in normal ovarian tissue are also found in association with benign and malignant tumors in contrast to their functions in normal tissues. Thus, we measured macrophage colony-stimulating factor (M-CSF) levels in the liquid contents of benign ovarian tumors--serous cystadenoma, mucinous cystadenoma, and mature cystic teratoma--and investigated whether M-CSF levels were associated with the histologic type of the ovarian tumors. METHODS: We enrolled 65 patients, 52 with benign ovarian tumor and 13 in the early postmenopausal period with symptoms of a menopausal disorder. Among the 52 patients with benign ovarian tumor, 16 had serous cystadenoma, 21 had mucinous cystadenoma, and 15 had mature cystic teratoma. Immediately after surgery, the liquid content was drawn from the ovarian tumor, then centrifuged, and the separated supernatant was stored at -30 degrees C. The M-CSF level was determined by the sandwich enzyme-linked immunosorbent assay method with use of three antibodies. RESULTS: The level of M-CSF was 12,513 U/mL (median) (range, 0-169,000 U/mL) in serous cystadenoma, 915 U/mL (0-82,500 U/mL) in mucinous cystadenoma, and 149 U/mL (0-6,230 U/mL) in mature cystic teratoma. The M-CSF levels increased significantly from mature cystic teratoma to mucinous cystadenoma to serous cystadenoma. The serum M-CSF levels were 308 to 499 U/mL in patients with benign ovarian tumor. The M-CSF levels did not differ significantly among the three groups. The serum M-CSF levels were 162 U/mL (0-473 U/mL) in menopausal patients. CONCLUSIONS: Elevation of levels of M-CSF varies according to histologic type in benign ovarian tumors. This implies that the antitumor activities of M-CSF for serous cystadenoma, mucinous cystadenoma, and mature cystic teratoma differ by histologic type.     

Elevated serum levels of macrophage colony-stimulating factor in patients with Kawasaki disease complicated by cardiac lesions.

OBJECTIVE: The main pathogenic characteristic of Kawasaki disease (KD) is the activation of mononuclear phagocytes. The cytokines produced by activated monocytes/macrophages elicit proinflammatory and prothrombotic responses in endothelial cells. Thus, we speculated that macrophage colony-stimulating factor (M-CSF), derived from monocytes/macrophages or vascular endothelial cells, might play an important role in the pathogenesis of the acute phase of KD. The aim of this study was to investigate the possible role of M-CSF in the pathogenesis of KD and to elucidate the relationship between serum M-CSF levels and clinical features and cardiac lesions. METHODS: Using ELISA, we serially assayed M-CSF and several cytokines, including interleukin-6, interleukin-8, tumor necrosis factor-alpha and interferon-gamma in the sera of 32 KD patients aged 2 months to 4 years. RESULTS: The serum M-CSF level during the first week of illness was significantly higher than during the second week or thereafter (first week, median 1710.0; second week, 1121.0; third week, 867.3; fourth week, 909.4 U/ml, p<0.001) in our KD patients. Serum M-CSF levels during the first week of illness were also higher in patients with mitral and/or aortic valvular insufficiency than in patients without cardiac complications. Furthermore, serum M-CSF levels in patients with persistent coronary dilatation were higher than in those with no cardiac complications. CONCLUSION: M-CSF plays a critical role in the pathogenesis of KD and can be used as an indicator for the risks of valvulitis and coronary arteritis.     

High serum levels of granulocyte-macrophage colony-stimulating factor in patients with liver cirrhosis and granulocytopenia

Summary Leucopenia is often observed in patients with liver cirrhosis. We measured levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with liver cirrhosis by a sensitive enzyme linked immunosorbent assay. Eight out of 22 patients with liver cirrhosis had detectable serum GM-CSF (range, 55 to 245 pg/ml:mean, 135 pg/ml). Serum GM-CSF was detected in all patients with a granulocyte count below 2.0 × 10⁹/l, but in only one patient with a granulocyte count above 2.0 × 10⁹/l. Haemoglobin concentration, platelet count, serum albumin, total bilirubin and aminotransferase levels did not correlate with serum GM-CSF levels. These findings may reflect a feedback mechanism between the number of circulating granulocytes and serum GM-CSF levels in patients with cirrhosis.     

巨噬细胞集落刺激因子与脊柱关节病发病机制相关性的初步探讨

目的通过检测脊柱关节病(SpA)患者血清和关节液中巨噬细胞集落刺激因子(M-CSF)的表达及其与SpA患者疾病活动的相关性来探讨M-CSF在SpA发病机制中的作用。方法用含有1 176个基因点阵的寡核苷酸基因芯片技术检测了11例SpA患者的滑膜组织和10名正常对照的外周血单个核细胞(PBMC)的基因表达谱。同时应用酶联免疫吸附试验(ELISA)检测了两组强直性脊柱炎(AS)患者血清中M-CSF的表达水平,一组是41例未用任何抗肿瘤坏死因子(TNF)-α等生物制剂治疗的AS患者血清,另一组是13例应用TNF-α抑制剂infliximab治疗前和治疗14周后的AS患者血清,同时检测了28名正常对照个体血清和15例SpA患者关节液中M-CSF的水平。结果关节液和外周血清中均可检测出M-CSF；41例未用任何生物制剂治疗的AS患者,其血清M-CSF的水平与AS疾病活动指数(BASDAI)具有明显相关性(r=0．41,P=0．004)；应用infliximab治疗14周后,AS患者BASDAI值比治疗前显著下降(P=0．000 07),但是M-CSF值下降不明显。结论M-CSF是研究SpA发病机制的一个肯定和有用的候选基因,其调节SpA的信号途径与TNF-α的作用途径不同,这有可能为开发新的治疗SpA的生物抑制剂提供理论基础。     

Direct interaction of proteoglycan macrophage colony-stimulating factor and basic fibroblast growth factor

The proteoglycan form of macrophage colony-stimulating factor (PG-M- CSF), but not M-CSF with a molecular weight of 85 kD (85-kD M-CSF), bound to immobilized basic fibroblast growth factor (bFGF), and, conversely, bFGF bound to immobilized PG-M-CSF, but not to the 85-kD M- CSF. PG-M-CSF has an additional amino acid sequence at its carboxyl terminus (part of a precursor sequence that is removed in 85-kD M-CSF by proteolytic processing) and it has one or two chondroitin sulfate glycosaminoglycan chains at the carboxyl terminus. Enzymatic removal of the chondroitin sulfate chain from PG-M-CSF had no effect on the binding between PG-M-CSF and bFGF. Ligand blotting analysis with radioiodinated bFGF showed that bFGF specifically bound to the polypeptide that corresponded to the carboxyl terminus of PG-M-CSF and was produced in Escherichia coli transfected with its gene. The exogeneous addition of heparan sulfate, which has strong affinity for bFGF, efficiently inhibited the binding between PG-M-CSF and bFGF. These results show that PG-M-CSF binds bFGF through its carboxyl terminal peptide and that the binding sites for PG-M-CSF and heparan sulfate on bFGF are located close together. PG-M-CSF also significantly reduced the mitogenic action of bFGF on Balb/c 3T3 mouse fibroblastic cells. Therefore, we conclude that PG-M-CSF not only binds bFGF, but also neutralizes the activity of the growth factor.