Distribution and comparison of receptors for leukemia inhibitory factor on murine hemopoietic and hepatic cells

Leukemia inhibitory factor (LIF) is a glycoprotein that induces the differentiation of the monocytic leukemia cell line M1 but suppresses the differentiation of totipotent embryonic stem cells. In an attempt to define the normal cellular targets for LIF, the distribution of LIF receptors within hemopoietic and hepatic tissue was analyzed by binding cells with radioiodinated LIF (¹²⁵I-LIF) and subsequently carrying out autoradiography. Autoradiography demonstrated that in each he-mopoietic tissue examined cells of monocyte/macrophage lineage were the primary cell type labeled with ¹²⁵I-LIF. Moreover, both fetal and adult parenchy-mal hepatocytes displayed higher levels of labeling than either monocytes or macrophages. The number of receptors per positive cell varied from 150 for bone marrow monocytes to 2,000 for adult hepatocytes. In each case, however, binding was of high affinity, with an apparent K_D of 34–100 pM, and binding was specific, since labeling was competed for by unlabeled LIF but not a range of other structurally unrelated growth and differentiation factors. It is suggested that LIF may play a role in regulating macrophage function and hepatic acute phase protein synthesis in response to infection.     

Uptake and degradation of 125I-labelled high density lipoproteins in rat liver cells in vivo and in vitro.

1. The uptake of 125I-labelled high density lipoproteins (HDL) in various organs of the rat was determined after an intravenous injection. The uptake of 125I-labelled polyvinylpyrrolidone in the same organs was determined in order to assess uptake by fluid endocytosis. The uptake/organ was highest for the liver. The adrenals showed the highest uptake/unit weight of the organs studied. The liver, the kidneys and the spleen showed comparable values for uptake/g of tissue. The uptake of 125I-labelled HDL exceeded by far that of 125I-labelled polyvinylpyrrolidone in the liver, the kidneys, the spleen and the adrenals, indicating that the uptake of 125I-labelled HDL was mediated by adsorptive endocytosis. 2. The in vivo uptake of 125I-labelled HDL was determined in purified hepatocytes and non-parenchymal cells prepared by collagenase perfusion of livers from animals after intravenous injections of 125I-labelled HDL. When expressed per cell, the hepatocytes and the non-parenchymal liver cells took up about the same amount of 125I-labelled HDL. 3. The in vitro uptake and degradation of 125I-labelled HDL in isolated rat hepatocytes was studied. The uptake at increasing concentrations of 125I-labelled HDL was saturable indicating uptake mediated through binding sites. 125I-labelled HDL were easily degraded by contaminating proteases from the perfusate. 4. Subcellular fractionation by isopycnic centrifugation indicated that the accumulation of 125I-labelled HDL did not take place in the lysosomes, but rather on the plasma membrane and possibly in the endosomes (phagosomes). 5. 125I-labelled HDL were internalized into the cells and degraded in the lysosomes. Leupetin and chloroquine, inhibitors of the lysosomal function effectively inhibited the formation of 125I-labelled acid-soluble radioactivity by the cells. Chloroquine, but not the protease inhibitor leupeptin, reduced the hydrolysis of the cholesteryl ester moiety of HDL.     

Uptake and processing of human platelet factor 4 by hepatocytes

We previously demonstrated rapid clearance of human platelet factor 4 (PF4) from rabbit and rat blood, its accumulation in the liver, and elimination of PF4 degradation products in urine. The purpose of the present experiments was to characterize interaction of PF4 with cultured rat hepatocytes. 125I-PF4 was taken up by hepatocytes reaching maximum at 180 min. The association of 125I-PF4 with hepatocytes was two times greater at 37 degrees C than at 4 degrees C. At 37 degrees C degradation of 125I-PF4 by hepatocytes was also observed as indicated by the increase of 125I-PF4 radioactivity soluble in 6% trichloroacetic acid. By contrast, no uptake of 125I-beta-thromboglobulin antigen was observed. Autoradiography demonstrated that short incubation (5-20 min) of 125I-PF4 with hepatocytes results in the association of 125I-radioactivity with cell membranes while after longer incubation (60 min) radioactivity was also localized in the endosomes. Heparin inhibited binding and uptake of 125I-PF4 radioactivity by hepatocytes. We propose that part of PF4 released in the circulating blood by activated platelets is bound to the surface of hepatocytes and that it is further processed by these cells.     

Preferential accumulation of radioactivity in rat kidneys after the administration of 125I-labelled Fab antidigitalis antibodies

125I-labelled Fab antidigitalis antibodies were administered i.p. to rats, whose organs were removed 20 h later and examined for radioactivity. Maximum radioactivity was found in the thyroid region, followed by the kidneys, liver, adrenals, heart, skeletal muscle and brain. The radioactivity of kidneys was greater than in any of the other organs except the thyroid, where it probably resulted from the uptake of radioiodine, released from the antibodies. After injection of Na125I there was no difference between the kidneys and the liver. In kidney homogenates, radioactivity was present both in the 100,000xg pellet and in the supernatant. The possibility of accumulation or production of the endogenous digitalis-like factor in the kidneys is discussed.     

Osteoblasts display receptors for and responses to leukemia-inhibitory factor

Specific binding of leukemia-inhibitory factor (LIF) to osteoblasts, but not multinucleated osteoclasts, was demonstrated by receptor autoradiography by using cells isolated from newborn rat long bones. The clonal rat osteogenic sarcoma cells, UMR 106-06, which have several phenotypic properties of osteoblasts, expressed 300 LIF receptors per cell, with an apparent KD of 60 pM. Treatment of calvarial osteoblasts or UMR 106-01 cells with LIF resulted in a dose-dependent inhibition of plasminogen activator (PA) activity. Both calvarial osteoblasts and osteogenic sarcoma cells were shown by Western blotting and reverse fibrin autography to produce plasminogen activator inhibitor-1 (PAI-1), the production of which was increased by LIF treatment. Northern blot analysis revealed that LIF treatment resulted in a rapid (peak 1 hour), dose-dependent increase in mRNA for PAI-1. LIF treatment of the preosteoblast cell line, UMR 201, enhanced the alkaline phosphatase response of these cells to retinoic acid. Each of the osteoblast-like cell types (calvarial osteoblasts, UMR 106-06, and UMR 201) was shown to produce LIF by bioassay and, by using the polymerase chain reaction (PCR), was shown to express low levels of mRNA for LIF. These data establish that cells of the osteoblast lineage are targets for LIF action. The reported anabolic effects of this cytokine on bone formation in vivo could be related to inhibition of protease activity. LIF may be an important paracrine modulator in bone, or perhaps an autocrine one, based on the evidence for its production by osteoblasts and osteoblast-like cells.     

Renal synthesis of leukaemia inhibitory factor (LIF), under normal and inflammatory conditions

Leukaemia inhibitory factor (LIF) is a pleiotropic cytokine that is particularly involved in nephrogenesis and repair of the extracellular matrix. Transgenic mice overexpressing LIF have mesangial proliferative glomerulonephritis. Also, during local inflammatory reactions, such as kidney graft rejection or urinary tract infections, urinary LIF excretion is enhanced. The aim of the study therefore was to study LIF production by normal and inflammatory diseased kidneys (glomerulonephritis or graft rejection), maintained in short cultures. To determine the responsibility of the kidney itself in LIF synthesis, we measured LIF secretion into the culture supernatants of human mesangial or renal tubular epithelial cells. Fragments from diseased kidneys, whether grafts or not, released more LIF than normal human kidney fragments, mesangial or renal tubular epithelial cells. However, LIF production was delayed in renal transplants compared to glomerulonephritic samples taken from untreated patients. In every case, LIF production was enhanced by interleukin 1beta (IL-1beta) and inhibited by IL-4 or dexamethasone, except in two severe rejection episodes. So, LIF appeared to respond to pro- and anti-inflammatory stimuli, in vitro and in vivo. Considering its biological effects, LIF could play a role in inflammatory renal diseases.     

Modulation of PDGF mediated osteoblast chemotaxis by leukemia inhibitory factor LIF

Cell migration is a key event in tissue repair and remodeling. PDGF, a growth factor for multiple target cells, has been shown to be a potent chemoattractant for a variety of mesenchymal cells. However, it is likely that PDGF-mediated cell migration will be influenced by other cytokines that can be produced during physiological and pathological conditions. Leukemia inhibitory factor (LIF), a cytokine that is produced by a variety of cells including osteoblasts, may promote bone formation, but the mechanism is not known. Since osteoblasts are responsible for laying down new matrix during skeletal remodeling, in this report we have examined whether PDGF or LIF influences the migration of osteoblasts. Among several cytokines and growth factors tested, only PDGF was able to elicit a major chemotactic (directed migration) and a minor chemokinetic (random-migration) response in osteoblasts. LIF alone was not active in either chemotaxis or chemokinesis but when included with PDGF it caused a reduction in chemokinesis. Further, pretreatment of osteoblasts with LIF caused an increase in PDGF-driven chemotaxis. Finally, osteoblasts exposed briefly to LIF synthesized a higher level of non-collagenous proteins upon further treatment with PDGF. These observations are consistent with a role for LIF in promoting bone formation, both by influencing directional migration of osteoblasts and in laying down new matrix. © 1996 Wiley-Liss, Inc.     

Protein clearance from the air spaces and lungs of unanesthetized sheep over 144 h

We studied the rate, the routes, and the mechanisms for protein clearance from the air spaces and lungs of 20 unanesthetized sheep over 144 h. We instilled 100 ml of autologous serum labeled with 125I-albumin into one lung. At the end of 24, 48, 96, or 144 h, the lungs were removed and the residual native protein and 125I-albumin in the air spaces were determined by bronchoalveolar lavage. Also the fraction of the instilled 125I-albumin remaining in the rest of the lung was measured in the lung homogenate. Clearance of the 125I-albumin from the lung into the plasma, lymph, thyroid, urine, and feces was also determined. The removal of both the 125I-albumin and the native protein from the air spaces was slow, following a monoexponential decline. The removal rate of the 125I-albumin from the air spaces was slightly but significantly faster (1.6%/h) than the clearance rate of the native protein (0.9%/h). Clearance of the 125I-albumin from the lung also followed a slow monoexponential decline at a rate of 1.4%/h. At all time periods, 75% of the 125I-albumin remaining in the lung was located in the air spaces, thus indicating that the pulmonary epithelium is the principal barrier to protein clearance from the normal lung. Macrophages appeared to play a minor role in alveolar protein clearance because the quantity of 125I-albumin present in the phagocytic cells in the air spaces was less than 1% of the instilled 125I-albumin at all time periods. However, macrophages may play some role in protein clearance after 48 h because we visualized phagolysosomes in macrophages, and there was an increase in free iodine in lung lavage, urine, thyroid, and feces after 48 h. However, gel electrophoretic studies showed that most of the 125I-albumin was cleared from the lung as an intact molecule, although only 24.7 +/- 4.7% of the 125I-albumin was cleared by the lymphatics.     

Insulin binding and degradation in isolated hepatocytes from streptozotocin injected rats

Isolated hepatocytes from streptozotocin injected rats bound the same amount of [125I]monoiodoinsulin as hepatocytes from control rats. Scatchard analysis confirmed that insulin receptor number and affinity were the same for both groups. Relatively more cell-associated radioactivity was located intracellularly in hepatocytes from streptozotocin injected rats. Pretreatment with chloroquine resulted in a smaller increase in intracellular [125I]monoiodoinsulin in cells isolated from streptozotocin injected rats than for control cells. These results suggest that intracellular insulin processing occurs more slowly in hepatocytes isolated from streptozotocin injected rats than from control rats.     

Stimulation of adenyl cyclase and fixation of iodine in human cancerous thyroid cells in culture

In primary cultures of cells from human thyroid cancer, functional activity was investigated by adenylate cyclase responsiveness and radioiodine uptake. In cells from well-differentiated follicular carcinomas (2 cases), TSH stimulation of cAMP accumulation is similar to that of normal thyroid cells. In contrast, in papillary carcinomas (11 cases), the mean dose-response curve is much lower than normal. In thyroid cancers, radioiodine uptake by the cells has been detected in some cases after 3 days of 125I incorporation. As previously observed, our results suggest the existence of a relationship between adenylcyclase responsiveness and 125I uptake by the cells.     

Characterization of the slowly dissociable human growth hormone binding component of isolated rat hepatocytes

Human growth hormone (hGH) bound to specific sites on rat hepatocytes. The time course of hGH dissociation was comprised of more than one component. Dissociation was resolved into rapid (t1/2 = 10.5 min) and slow (t 1/2 = 6.4 h) fractions. The amount of slowly dissociable hormone increased for the first 75 min during which time cells and [125I]hGH associated. Subsequently, the amount of slowly dissociable hGH was constant. The time courses of hGH receptor binding and subsequent retention of slowly dissociable label were similar. The capacity of hepatocytes to accumulate slowly dissociable label was saturated by hGH over the same concentration range as the high-affinity binding site (KD approximately 2 nM). This suggested that a receptor-mediated process was responsible for the accumulation of slowly dissociable hGH. Rapidly dissociable label was intact [125I]hGH and fragments resulting from growth hormone degradation. Slowly dissociable hGH recovered from hepatocytes by acid extraction was intact and immunocompetent. There was a large increase in the extent of [125I]hGH degradation between 23 and 37 degrees C. Over this temperature range, the proportion of hGH not in rapid equilibrium with the medium decreased. High concentrations of hGH decreased the amount of slowly dissociable [125I]hGH retained by hepatocytes by competing for high-affinity sites. The interaction of [125I]hGH with low-affinity degradative systems was favored by the presence of hGH. The temperature and concentration dependencies of hGH retention and degradation distinguished these proceses.     

Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat

The plasma half-life of recombinant human interleukin-6 (rhIL-6) was determined in rats by measuring the disappearance of the biological activity as well as of the radioactivity of 125I-rhIL-6 from the circulation. The kinetics of clearance were biphasic. It consisted of a rapid initial disappearance corresponding to a half-life of 3 min, and of a second slow one corresponding to a half-life of about 55 min. By cellulose-acetate electrophoresis it was shown that rhIL-6 binds to a plasma protein resulting in a complex migrating in the beta-gamma region; 20 min after intravenous injection, about 80% of the 125I-rhIL-6 that had disappeared from the circulation was found in the liver. 125I-rhIL-6 was exclusively localized on the surface of parenchymal cells suggesting the existence of an interleukin-6 receptor on the hepatocytes.     

Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections

It is well known that hepatitis B virus infections can be transient or chronic, but the basis for this dichotomy is not known. To gain insight into the mechanism responsible for the clearance of hepadnavirus infections, we have performed a molecular and histologic analysis of liver tissues obtained from transiently infected woodchucks during the critical phase of the recovery period. We found as expected that clearance from transient infections occurred subsequent to the appearance of CD4(+) and CD8(+) T cells and the production of interferon gamma and tumor necrosis factor alpha in the infected liver. These events were accompanied by a significant increase in apoptosis and regeneration of hepatocytes. Surprisingly, however, accumulation of virus-free hepatocytes was delayed for several weeks following this initial influx of lymphocytes. In addition, we observed that chronically infected animals can exhibit levels of T-cell accumulation, cytokine expression, and apoptosis that are comparable with those observed during the initial phase of transient infections. Our results are most consistent with a model for recovery predicting replacement of infected hepatocytes with regenerated cells, which by unknown mechanisms remain protected from reinfection in animals that can be cured.     

Renal uptake and degradation of trapped-label insulin

In order to study the kinetics of insulin degradation in the kidneys and liver, insulin was labelled by a trapped-label procedure and injected into rats. In contrast to conventional 125I-insulin, the trapped-label preparation allows quantitative measurements of the extent of degradation in vivo because the final degradation products do not leave the cells. One hour after injection, the amount of radioactivity in the kidneys from a trace dose of trapped-label insulin was 10 times higher that from conventionally labelled insulin; over 80% of the increase was due to low molecular weight degradation products which were retained in the kidneys. The amount of acid-precipitable radioactivity in the blood was the same for both labelled preparations, indicating that their rates of clearance were similar. In the kidney, we detected no degradation products of molecular weight intermediate between intact insulin and the end products of proteolysis. After 2 h, 33% of the injected dose remained in the kidneys and only 13% in the liver. Over 80% of the renal radioactivity was sedimentable in an isotonic density gradient, indicating that intact insulin, as well as degradation products in the cells, were enclosed within membrane-bound vesicles.     

Interactions between tissue-type plasminogen activator and extracellular matrix-associated plasminogen activator inhibitor type 1 in the human hepatoma cell line HepG2

Hepatic parenchymal cells contribute to the clearance of circulating tissue-type plasminogen activator (t-PA) in vivo. The hepatocyte extracellular matrix is interposed between the endothelial-lined sinusoids and the parenchymal cell surface and thus may influence t-PA clearance. To test this hypothesis, the well differentiated human hepatoma cell line HepG2 was used to characterize the role of extracellular matrix in t-PA clearance in vitro. Previous studies with these cells demonstrated their capacity for specific catabolism of t-PA in a system modulated by plasminogen activator inhibitor type 1 (PAI-1). In the present study the extracellular matrix growth substratum of HepG2 cells is shown to contain active PAI-1. PAI-1 is distributed in a punctuate pattern throughout the substratum. Components of the substratum confer stability to active PAI-1 for intervals of at least 24 h. Exposing substratum to 125I-t-PA leads rapidly to the formation and release of a sodium dodecyl sulfate-stable 95-kDa 125I-t-PA.PAI-1 complex. In comparison, cell monolayers have the additional capacity for specific binding of the complex. However, PAI-1 is not detected at the surface of HepG2 cells in suspension, suggesting that 125I-t-PA.PAI-1 complexes form in substratum and subsequently bind to cells. Specific binding of performed 125I-t-PA.PAI-1, but not 125I-t-PA, was demonstrated for HepG2 cells in suspension. These results suggest that components of extracellular matrix participate in the clearance of t-PA by hepatocytes.     

Improvement of pharmacokinetics of radioiodinated Tyr(3)-octreotide by conjugation with carbohydrates

Among a variety of other factors, the clearance kinetics and routes of excretion of radiopharmaceuticals are of crucial importance for early and high tumor/background ratios and thus signal intensity in diagnostic imaging by single photon emission tomography (SPECT) or positron emission tomography (PET). To overcome the unfavorable pharmacokinetics of radiohalogenated octreotide analogues, we evaluated three carbohydrated conjugates of Tyr(3)-octreotide (TOC). Glucose ([(125)I]Gluc-TOC), maltose ([(125)I]Malt-TOC), and maltotriose ([(125)I]Mtr-TOC) derivatives of [(125)I]TOC were synthesized via Maillard reaction and subsequent radioiodination. In cells transfected with sst1-sst5, I-Malt-TOC, and I-Mtr-TOC show sst-subtype binding profiles similar to I-TOC with high affinity for sst2. Comparative biodistribution studies 10, 30, and 60 min pi in nude mice bearing rat pancreatic tumor xenografts showed fast blood clearance for all glycosylated derivatives. Due to their markedly increased hydrophilicity, [(125)I]Gluc-TOC and [(125)I]Malt-TOC were mainly cleared via the kidneys, which led to a significant decrease in activity accumulation in liver and intestine (5.3 and 1.4 versus 10.6%ID/g for [(125)I]TOC in the liver, 1.7 and 1.0 versus 3.8%ID/g for [(125)I]TOC in the intestine 60 min pi). For all compounds, hydrophilicity and uptake in liver and intestines correlate. Uptake of the carbohydrate conjugates in the kidney was comparable. Compared to the parent compound, the accumulation of the carbohydrated compounds in sst-rich tissues (pancreas, adrenals) was increased by a factor of 1.5-3.5. While tumor uptake of [(125)I]TOC (6.7 +/- 2.6%ID/g), [(125)I]Malt-TOC (5.3 +/- 1.9%ID/g), and [(125)I]Mtr-TOC (4.9 +/- 2.2%ID/g) at 30 min postinjection was comparable, accumulation of [(125)I]Gluc-TOC was significantly increased (10.1 +/- 2.8%ID/g at 30 min pi). Somatostatin receptor specificity of tumor uptake was confirmed by pretreatment, competition, and displacement experiments in vivo using 0.8 mg TOC/kg and gamma-camera imaging. Glycosylation proved to be a powerful tool for the development of high affinity sst ligands with excellent excretion profiles and improved tumor accumulation.     

Activity of thyroid stimulating antibody and thyroid stimulation blocking antibody determined by radioiodine uptake into FRTL-5 cells

To investigate the pathophysiology of patients with autoimmune thyroid diseases, we measured serum thyroid stimulating antibody (TSAb) activity and thyroid stimulation blocking antibody (TSBAb) activity by determining the radioiodine (125I) uptake into FRTL-5 cells. FRTL-5 cells were pre-incubated for seven days with 5H medium and then incubated for 48 hours with patients' crude IgG prepared by polyethylene glycol precipitation. In order to measure TSBAb, 10 microU/ml TSH was also added. 125I was added one hour before the end of the 48 hour incubation period. After the incubation, the medium was aspirated, and the radioactivity in the cells was counted. In patients with untreated hyperthyroid Graves' disease, TSAb was detectable in 18 of 20 patients, the detectability being 90%, and activity showed a statistically significant positive correlation with TSAb activity determined by c-AMP accumulation. Out of 41 patients with hypothyroidism, TSBAb determined by 125I uptake was positive in six cases, the detectability being 14.6%. The inhibition of 125I uptake by one of these six IgGs was suggested to be at the TSH receptor level because it inhibited TSH induced c-AMP accumulation and showed positive thyrotropin binding inhibitor immunoglobulin (TBI I) activity, but did not inhibit the forskolin- and (Bu)2cAMP-induced 125I uptake. Inhibition of another IgG was suggested at the post-receptor level because it did not inhibit TSH induced cAMP accumulation and showed negative TBI I activity, but inhibited forskolin- and (Bu)2cAMP-induced 125I uptake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic lipase in the rat ovary. Ovaries cannot synthesize hepatic lipase but accumulate it from the circulation

Hepatic lipase is proposed to have a role in steroidogenesis through its involvement in the metabolism of high density lipoproteins. We examined the activity, synthesis, distribution, and uptake of this enzyme and assessed the content of its mRNA in luteinized ovaries. We found that during peak steroidogenesis, ovaries of pregnant mare's serum gonadotropin-human chorionic gonadotropin-treated immature rats contained heparin-releasable hepatic lipase-like activity which was neutralized in a dose-dependent manner by purified antibodies to hepatic lipase isolated from post-heparin perfusates of rat livers. Quantitative immunoelectron microscopy revealed that ovarian hepatic lipase occurred along endothelial cells and was 3-fold more abundant in blood vessels of corpora lutea than those of stroma. However, hepatic lipase was not synthesized by the ovary since radiolabeled enzyme was not immunoisolated from the medium of dispersed luteinized granulosa cells incubated with [35S]methionine whereas it was present in the medium of control cells (hepatocytes). Similarly, hepatic lipase mRNA was detectable in liver but not ovaries or kidneys by Northern or slot blot analyses or by the polymerase chain reaction. Finally, 125I-labeled hepatic lipase injected into tail veins was quickly cleared from the systemic circulation, accumulating in liver, ovaries, kidneys, and spleen. Subsequent heparin injection caused rapid reappearance of radioactivity in the bloodstream and a marked decline of radiolabel in liver and ovaries but a modest decrease of that in kidneys and none in spleen. Exogenous 125I-bovine serum albumin also accumulated in all four organs but was not displaced from liver or ovaries by subsequent administration of heparin. Taken together, these data suggest that steroidogenically active ovaries possess but do not synthesize hepatic lipase. Instead, hepatic lipase originating elsewhere, presumably in the liver, is accumulated from the circulation at heparin-sensitive sites in ovarian blood vessels.     

Interleukin-11 regulates the hepatic expression of the same plasma protein genes as interleukin-6.

Treatment of rat hepatoma H-35 cells with purified human recombinant interleukin-11 (IL-11) resulted in the stimulated production of several major acute phase plasma proteins. The qualitative and quantitative changes were comparable to those mediated by IL-6 or leukemia inhibitor factor (LIF). Like IL-6, IL-11 acted synergistically with IL-1 on type 1 acute phase proteins. The combination of IL-11 and dexamethasone yielded a magnitude of stimulation which was more similar to the combination of LIF and dexamethasone than IL-6 and dexamethasone. IL-11 elicited in treatment of primary cultures of rat hepatocytes a qualitative change of plasma protein production which was similar to that in H-35 cells. Comparison of rat and human hepatoma cells indicated that the IL-11 response did not correlate with that of IL-6 or LIF, suggesting that the action of IL-11 was mediated by an IL-11-specific receptor system. However, the intracellular transduction of the IL-11, IL-6, and LIF signals to the acute phase protein genes seems to rely, in part, on common elements as judged from their stimulatory effects on the transfected expression vector containing the IL-6 response element of the rat beta-fibrinogen gene. The finding that IL-11 shares liver-regulating properties with IL-6 and LIF suggests that IL-11 has the potential of contributing to the control of systemic homeostasis and hepatic acute phase response.