Negative Acute Phase Proteins Research Articles

Citrulline and albumin as biomarkers for gastrointestinal mucositis in recipients of hematopoietic SCT

Gastrointestinal (GI) mucositis is a common side effect of intense chemotherapy to prepare patients for hematopoietic SCT. Measuring intestinal damage objectively remains difficult, and clinicians often rely on albumin levels as an indicator of GI mucositis, but citrulline might be a more specific marker, which has in the past been shown to correlate with clinical signs of GI mucositis. We evaluated the courses of albumin and citrulline following different conditioning regimens for SCT and studied their relatedness to the subsequent inflammatory response using C-reactive protein. Patterns of albumin and citrulline differed significantly between myeloablative and non-myeloablative conditioning regimens. After myeloablative regimens, decreasing citrulline levels preceded the occurrence of inflammation unlike albumin levels, which decreased thereafter. Albumin levels were greatly influenced by inflammation, confirming it to be a 'negative acute-phase protein', whereas citrulline levels were not. Citrulline appeared to be a better biomarker of GI mucositis than albumin. Measuring citrulline might prove useful in clinical decision making, in identifying GI mucositis, and it would also be of interest to see how it compares with other biomarkers in the setting of acute GI GVHD.

Effect of Acute Thermal Injury in Status of Serum Vitamins, Inflammatory Markers, and Oxidative Stress Markers

The objective of this study was to evaluate the vitamin status, inflammatory markers, and oxidative stress markers in adult patients up to 3 days after thermal injury. This prospective study was conducted with 11 patients 24 to 72 hours after thermal injury (Burn Group), total surface area ranging from 10 to 41%, 34.3 ± 9.3 years, 82% of males, body mass index of 22.3 ± 2.9 kg/m(2). We included 11 healthy adults (Control Group), 36.5 ± 7.6 years, 73% of males, and body mass index of 23.8 ± 2.5 kg/m(2). Laboratory data were measured (plasma total protein, albumin, transferrin, lymphocyte counts, zinc, and iron), as well as serum vitamins (folic acid, vitamin B12, and vitamins A, C, and E), inflammatory stress markers (C-reactive protein, ferritin, and acid α1-glycoprotein) and oxidative stress markers such as glutathione peroxidase (GPx) and thiobarbituric acid reactive substances. The inflammatory stress was characterized by lower levels of total protein (median difference 1.2 g/dL, 95% CI: 0.4-2.1) and albumin (median difference 0.9 g/dL, 95% CI: 0.5-1.5), and higher levels of C-reactive protein (median difference -8.12 mg/dL, 95% CI: -11.62 to 4.61) and α-1 glycoprotein acid (median difference -28.56 mg/dL, 95% CI: -51.57 to -5.07) in burn patients. Decreased serum levels of vitamin A (median difference 1.10 μmol/L, 95% confidence interval [CI]: 0.42-1.66) and vitamin C (median difference 0.82 mg/dL, 95% CI: 0.50-1.04) were also detected. There was no statistical evidence of difference in the serum levels of glutathione peroxidase and thiobarbituric acid reactive substances between burn patients and controls, respectively. Even though there is an inflammatory stress, the obtained data showed that oxidative stress markers are normal 24 to 72 hours after burn injury. The decrease in negative acute phase protein may account for the diminished serum levels of vitamin A, which seems to be related to inflammatory stress. The marked decrease in the serum levels of vitamin C can be justified by augmented cutaneous loss and consumption in the regeneration of vitamin E.

Serum Protein Electrophoresis by Using High-resolution Agarose Gel in Clinically Healthy andAspergillusSpecies-infected Falcons

Serum protein electrophoresis has gained importance in avian medicine during the past decade. Interpretation of electrophoretic patterns should be based on species-specific reference intervals and the electrophoresis gel system. In this study, serum protein electrophoresis by using high-resolution agarose gels was performed on blood samples collected from 105 falcons, including peregrine falcons (Falco peregrinus), gyrfalcons (Falco rusticolus), saker falcons (Falco cherrug), red-naped shaheens (Falco pelegrinoides babylonicus), and hybrid falcons, that were submitted to the Dubai Falcon Hospital (Dubai, United Arab Emirates) between 2003 and 2006. Reference values were established in clinically healthy birds and compared with values from falcons infected with Aspergillus species (n = 32). Falcons with confirmed aspergillosis showed significantly lower prealbumin values, which is a novel finding. Prealbumin has been documented in many avian species, but further investigation is required to illuminate the diagnostic significance of this negative acute-phase protein.

Ferroportin-1 behaves as a negative acute phase protein in rat liver

Ferroportin-1 behaves as a negative acute phase protein in rat liver

Association of serum fetuin-A levels with heart valve calcification and other biomarkers of inflammation among persons with acute coronary syndrome

Fetuin-A is a multifunctional hepatic secretory protein that inhibits dystrophic vascular and valvular calcification. Our aim was to evaluate the relationship among fetuin-A levels, heart valve calcification and other biomarkers of inflammation in patients with acute coronary syndrome (ACS). The associations among serum fetuin-A concentrations, mitral annular (MAC) and aortic valve calcification and other biomarkers of inflammation (hs-CRP, ferritin, fibrinogen, white blood cell count (WBC), erythrocyte sedimentation rate (ESR), albumin levels) were evaluated in ACS patients and healthy controls. The study included 95 patients (mean age 61.8 ± 12.10 years) and 81 healthy controls (mean age 48.33 ± 9.19 years). Fetuin-A levels were significantly lower in patients with ACS than in healthy controls (0.76 ± 0.23 and 1.10 ± 0.45 g/L, respectively; p < 0.001). Fetuin-A was lower in patients with mitral annular calcification (p = 0.007) and aortic (p = 0.001) valve calcification. In patients with ACS, there was a negative correlation among serum urea (r = -0.377; p < 0.001) and creatinine (r = -0.232; p = 0.024) levels and fetuin-A, and a negative correlation among WBC (r = -0.156; p = 0,132), ESR (r = -0.214; p = 0.037), hs-CRP (r = -0.220; p = 0.032) levels and fetuin-A. A positive correlation was seen between albumin and fetuin-A (r = 0.362; p < 0.001). Multivariate logistic regression analysis revealed that fetuin-A was the variable that had a significant effect on ACS (p = 0.020 OR = .015; (95% CI)(0.000-0.520). Fetuin-A levels decrease in patients with acute coronary syndromes, independent of heart valve calcification. Fetuin-A may therefore act as a negative acute phase protein after myocardial infarction.

Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins

Liver is the central organ of iron metabolism. During acute-phase-response (APR), serum iron concentration rapidly decreases. The current study aimed to compare expression and localization of iron transport protein ferroportin-1 (Fpn-1) and of other iron import proteins after experimental tissue damage induced by injecting turpentine oil in the hind limbs of rats and mice. Serum and spleen iron concentration decreased with an increase in total liver, cytoplasmic and nuclear iron concentration. In liver, mRNA amount of Fpn-1, Fpn-1a, Fpn-1b, HFE, hemojuvelin (HJV) and hephaestin (heph) genes showed a rapid decrease. Hepcidin, divalent metal transporter-1 (DMT-1), transferrin (Tf) and Tf-receptor-1 (TfR1), TfR-2 (TfR2) gene expression was increased. Western blot analysis of liver tissue lysate confirmed the changes observed at mRNA level. In spleen, a rapid decrease in gene expression of Fpn-1, Fpn-1a, Fpn-1b, DMT-1, Tf, TfR1 and TfR2, and an increase in hepcidin was observed. Immunohistochemistry of DMT-1 and TfR2 were mainly detected in the nucleus of rat liver and spleen, whereas TfR1 was clearly localized in the plasma membrane. Fpn-1 was mostly found in the nuclei of liver cells, whereas in spleen, the protein was mainly detected in the cell membrane. Western blot analysis of liver fractions confirmed immunohistochemical results. In livers of wild-type mice, gene expression of Fpn-1, Fpn-1a and Fpn-1b was downregulated, whereas hepcidin gene expression was increased. In contrast, these changes were less pronounced in IL-6ko-mice. Cytokine (IL-6, IL-1β and TNF-α) treatment of rat hepatocytes showed a downregulation of Fpn-1, Fpn-1a and Fpn-1b, and upregulation of hepcidin gene expression. Moreover, western blot analysis of cell lysate of IL-6-treated hepatocytes detected, as expected, an increase of α2-macroglobulin (positive acute-phase protein), whereas albumin (negative acute-phase protein) and Fpn-1 were downregulated. Our results demonstrate that liver behaves as a ‘sponge' for iron under acute-phase conditions, and Fpn-1 behaves as a negative acute-phase protein in rat hepatocytes mainly, but not exclusively, because of the effect of IL-6. These changes could explain iron retention in the cytoplasm and in the nucleus of hepatocytes during APR.

Anti-Inflammatory Role of Fetuin-A in Injury and Infection

Infection and injury are two seemingly unrelated processes that often converge on common innate inflammatory responses mediated by pathogen- or damage-associated molecular patterns (PAMPs or DAMPs). If dysregulated, an excessive inflammation manifested by the overproduction and release of proinflammatory mediators (e.g., TNF, IFN-γ, and HMGB1) may adversely lead to many pathogenic consequences. As a counter-regulatory mechanism, the liver strategically re-prioritizes the synthesis and systemic release of acute phase proteins (APP) including the fetuin-A (also termed alpha-2-HS-glycoprotein for the human homologue). Fetuin-A is divergently regulated by different proinflammatory mediators, and functions as a positive or negative APP in injury and infection. It not only facilitates anti-inflammatory actions of cationic polyamines (e.g., spermine), but also directly inhibits PAMP-induced HMGB1 release by innate immune cells. Peripheral administration of fetuin-A promotes a short-term reduction of cerebral ischemic injury, but confers a long-lasting protection against lethal endotoxemia. Furthermore, delayed administration of fetuin-A rescues mice from lethal sepsis even when the first dose is given 24 hours post the onset of disease. Collectively, these findings have reinforced an essential role for fetuin-A in counter-regulating injury- or infection-elicited inflammatory responses.

Fetuin A: a new neuroprotective serum protein?

Aims: Fetuin A is a serum protein, essential for mineral homeostasis, showing immunomodulatory functions mediated by spermine-like polycations as well as TGF beta. It was neuroprotective in a rat model of acute stroke and reduces lethality after systemic LPS challenge. Serum fetuin A concentrations are highest during early intrauterine life and are depressed during acute phase (negative acute phase protein). Expression of fetuin A in the preterm brain has already been shown. This study aimed at specifying the cerebral expression pattern of fetuin A.

Albumin in early septic shock resuscitation: examination of plasma and urine inflammatory markers

A recent meta-analysis has suggested that albumin may be beneficial in sepsis; however, there is no clear biological rationale for the pharmacological use of this negative acute-phase protein. Our objective was to describe the temporal production of plasma and urine biomarkers in a pilot study of early septic shock patients resuscitated with either 5% albumin or normal saline.

Postoperative Aseptic Intracranial Granuloma: The Possible Influence of Fluid Hemostatics

Background. Numerous reports have demonstrated how postoperative intracranial granulomas can often mimic neoplasm clinically, radiologically, and even macroscopically. Herein we present an unusual case of postsurgical intracranial aseptic granuloma secondary to a chronic inflammatory reaction without any identifiable retained foreign body. Case Description. A 71-year-old patient started complaining of severe headache seven months after surgical excision of WHO Grade I right frontal falx meningioma. CT and MRI scans disclosed a contrast-enhanced lesion with diffuse mass effect in the previous surgical site. The lesion was resected; intraoperative finding and histological specimens led to the diagnosis of postoperative granuloma, likely expression of a glial reaction to the fluid absorbable hemostatics applied in the surgical site after meningioma excision. The possible granuloma-inducing materials and the timing of granuloma formation are discussed. Conclusion. A comprehensive analysis of clinical and neuroradiological data, as well as results of blood tests including positive and negative acute phase proteins, is mandatory to raise the suspicion of postoperative granuloma. The treatment options should be evaluated on a case-by-case basis, with a conservative attitude being the one of choice only for patients without progressive neurological deficit. Alternatively, aggressive surgical treatment and histopathological examination should be advocated.

Decreased plasma concentrations of apolipoprotein M in sepsis and systemic inflammatory response syndromes

IntroductionApolipoprotein M (apoM) is present in 5% of high-density lipoprotein (HDL) particles in plasma. It is a carrier of sphingosine-1-phosphate (S1P), which is important for vascular barrier protection. The aim was to determine the plasma concentrations of apoM during sepsis and systemic inflammatory response syndrome (SIRS) and correlate them to levels of apolipoprotein A-I (apoA1), apolipoprotein B (apoB), HDL-, and low-density lipoprotein (LDL)-cholesterol.MethodsPlasma samples from patients with (1), severe sepsis with shock (n = 26); (2), severe sepsis without shock (n = 44); (3), sepsis (n = 100); (4), infections without SIRS (n = 43); and (5) SIRS without infection (n = 20) were analyzed. The concentrations of apoM, apoA1, and apoB were measured with enzyme-linked immunosorbent assays (ELISAs). Total, HDL-, and LDL-cholesterol concentrations were measured with a commercial HDL/LDL cholesterol test.ResultsApoM concentrations correlated negatively to acute-phase markers. Thus, apoM behaved as a negative acute-phase protein. Decreased values were observed in all patient groups (P < 0.0001), with the most drastic decreases observed in the severely sick patients. ApoM levels correlated strongly to those of apoA1, apoB, HDL, and LDL cholesterol. The HDL and LDL cholesterol levels were low in all patient groups, as compared with controls (P < 0.0001), in particular, HDL cholesterol. ApoA1 and apoB concentrations were low only in the more severely affected patients.ConclusionsDuring sepsis and SIRS, the plasma concentrations of apoM decrease dramatically, the degree of decrease reflecting the severity of the disease. As a carrier for barrier-protective S1P in HDL, the decrease in apoM could contribute to the increased vascular leakage observed in sepsis and SIRS.

Metabolic stress and inflammatory response in high-yielding, periparturient dairy cows

Increased disease rates are commonly reported among high-yielding dairy cows in the transition period, extending from 3weeks before to 3weeks after calving, and characterized by the occurrence of an inflammatory response in terms of both positive and negative acute phase proteins (APP+ and APP−). To determine the above inflammatory response, the authors had developed the Liver Functionality Index (LFI), which defines the above condition on the basis of some APP− responses (albumin, cholesterol sensu stricto+bilirubin) during the first month of lactation. In this respect, low LFI values are associated to a high inflammatory response and vice versa. The relationship between LFI and inflammatory cytokine response was investigated from day −28 to day +28 with respect to calving in 12 periparturient dairy cows showing the six highest and six lowest LFI values within a cohort of 54 high-yielding dairy cows. The hypothesis being tested was that LFI and APP− on the whole could be used as readout of successful vs. non-successful adaptation to the transition period, with a strong association to disease occurrence. In fact, low LFI cows experienced many more disease cases (13 vs. 3 in high LFI Group) and related drug treatments till day +28. Interleukin-6 (IL-6) serum concentrations were always higher in low LFI cows (P<0.05 on day +28). The greater IL-6 levels were correlated with higher ceruloplasmin (APP+) and lower lysozyme serum concentrations (P<0.05 and <0.1, respectively). This latter finding was correlated with a clear role in vitro of lysozyme in a dose-dependent modulation of the inflammatory response of swine intestinal epithelial cells and bovine peripheral blood mononuclear cells. Hematological examinations showed no significant differences between the two groups under study. On the whole, our results indicate that LFI and LFI-related parameters could be used to identify cows at risk in the transition period toward an improved farm management. Also, our study indicates that disease cases in periparturient, high-yielding dairy cows are correlated with signs of accentuated IL-6 response and other markers of inflammatory phenomena. These likely start in the late lactation period or around dry-off, as suggested by our prepartal data, and proceed at much greater levels after calving.

ACUTE PHASE PROTEIN RESPONSE IN THE CAPYBARA (HYDROCHOERUS HYDROCHAERIS)

We evaluated the acute phase protein response in capybaras (Hydrochoerus hydrochaeris). Three animal groups were used: 1) healthy animals (n=30), 2) a group in which experimental inflammation with turpentine was induced (n=6), and 3) a group affected with sarcoptic scabies (n=14) in which 10 animals were treated with ivermectin. Haptoglobin (Hp), acid-soluble glycoprotein (ASG) and albumin were analyzed in all animals. In those treated with turpentine, Hp reached its maximum value at 2 wk with a 2.7-fold increase, whereas ASG increased 1.75-fold and albumin decreased 0.87-fold 1 wk after the induction of inflammation. Capybaras affected with sarcoptic scabies presented increases in Hp and ASG of 4.98- and 3.18-fold, respectively, and a 0.87-fold decrease in albumin, compared with healthy animals. Haptoglobin and ASG can be considered as moderate, positive acute phase proteins in capybaras because they showed less than 10-fold increases after an inflammatory process and reached their peak concentrations 1 wk after the induction of inflammation. Conversely, albumin can be considered a negative acute phase protein in capybaras because it showed a reduction in concentration after inflammatory stimulus.

Acute phase protein concentrations in colostrum-deprived pigs immunized with subunit and commercial vaccines against Glässer's disease

Haemophilus parasuis is the etiological agent of Glässer's disease, which is characterized by fibrinous polyserositis, polyarthritis and meningitis in pigs. This study was focused on the characterization of the acute-phase response after immunization and infection of colostrum-deprived pigs with H. parasuis serovar 5, by measuring serum concentrations of three positive acute-phase proteins (APPs) (pig major acute-phase protein pig, MAP; haptoglobin, HPG; C-reactive protein, CRP) and one negative APP (apolipoprotein A-I, ApoA-I). Six experimental groups were established: a non-immunized but infected control group (CTL); two groups immunized with either a recombinant transferrin-binding protein (Tbp) A or TbpB fragment from H. parasuis Nagasaki strain (rTbpA and rTbpB, respectively); two groups immunized with native outer membrane proteins with affinity to porcine transferrin (NPAPT), one of them inoculated intramuscularly (NPAPTim) and the other intratracheally (NPAPTit), and the last group receiving a commercially available bacterin (PG). The greatest concentrations of the three positive APPs and the lowest concentration of the negative APP were detected in CTL group, as well as in those animals belonging to rTbpA or rTbpB groups that died in response to challenge. Significant differences ( P < 0.005) were found in these groups when comparing challenge with the following days after it. However, no significant differences were seen for the remaining vaccinated groups (NPAPTim, NPAPTit and PG), which were effectively protected against Glässer's disease. Therefore, APPs could be used as useful biomarkers for both evaluating disease progression and determining vaccination effectiveness.

Acute Phase Response of Selenium Status and Glutathione Peroxidase Activity in Blood Plasma Before and After Total Knee Arthroplasty Surgery

Several studies show the consistent results of the decrease in plasma or serum selenium (Se) after surgery, and the change is suggested to be a negative acute phase response of Se to the surgical inflammation. Plasma glutathione peroxidase (GPx), which is included in the acute phase response proteins, is a selenoenzyme. However, previous studies failed to show any changes in GPx activity before and after surgery. In the present study, we investigated the Se- and selenoenzyme responses that accompany the acute inflammatory reactions during and following major surgery. Patients who underwent elective total knee arthroplasty surgery due to knee osteoarthritis at the Department of Orthopaedic Surgery at Gunma University Hospital in Japan were studied. The plasma Se concentration was determined, and the activity of plasma GPx was measured. C-reactive protein (CRP), albumin, blood urea nitrogen (BUN), and white blood cell (WBC) count were also analysed. Increases in the inflammatory biomarkers of CRP and WBC showed inflammatory reactions with the surgery. A significant increase in plasma GPx activity (p < 0.05) and decreases in the plasma Se concentration (p < 0.05) and in serum albumin (p < 0.05) after surgery were observed. Since albumin is a Se-containing protein and represents a negative acute phase protein that provides amino acids for the production of other series of acute phase proteins, the present results suggest that there is a redistribution of plasma Se to GPx that occurs as an acute phase response, and the source of Se for GPx could be, at least partly, from albumin.

C-reactive protein/albumin ratio at ICU discharge as a predictor of post-ICU death: a new useful tool

There are classical predictors of death after ICU discharge, such as age, severity of disease and level of nursing care. CRP concentrations at discharge have also been reported as a predictor of in-hospital outcome, but with controversial results. Considering that albumin is a negative acute-phase protein and its decrease may be an indicator of disease severity, we hypothesized that the CRP/albumin ratio could be a marker of unfavorable outcomes in the post-ICU period.

The diagnostic value of determination of positive and negative acute phase proteins in milk from dairy cows with subclinical mastitis

Currently, somatic cell count (SCC) and bacterial culture are considered as the gold standard methods for the diagnosis of bovine subclinical mastitis. However, SCC has a low diagnostic accuracy. Therefore, for identification of infected animals, new biomarkers with high diagnostic accuracy are needed. Acute phase proteins (APPs) are proteins that are increased (positive APPs) or decreased (negative APPs) in response to inflammation. The objective of this study was to determine the diagnostic value of milk APPs for the diagnosis of subclinical mastitis in dairy cows. A total of 90 clinically healthy cows were randomly selected. Of these, 52 cows were considered subclinical mastitic based on a SCC higher than 130 × 1,000 cells/mL of milk and positive bacterial culture results of milk samples obtained from at least one of the quarters. Milk amyloid A (MAA) concentration was measured using a commercial ELISA kit and albumin, α-lactalbumin, β-lactoglobulin, and immunoglobulin (Ig) were measured in the whey samples by the use of cellulose acetate electrophoresis. Diagnostic sensitivity and specificity and cutoff points for each test were determined via receiver-operating characteristics analysis. Significant (P 1.6 mg/L. The results of this study showed that determination of MAA can be used as a reliable method for the diagnosis of bovine subclinical mastitis.

인간 호중구의 세포사멸과 시토카인 분비에 대한 아포지방단백 A-I의 영향

Apolipoprotein A-I (apoA-I) has anti-inflammatory and anti-oxidative properties. This study was designed to investigate whether apoA-I affects apoptosis and cytokine production of human blood neutrophils in an in vitro culture system. Spontaneous apoptosis of neutrophils was significantly delayed by apoA-I. In addition, high density lipoprotein containing apoA-I also delayed apoptosis of neutrophils. Apoptosis of neutrophils was inhibited by anti-scavenger receptor type B-I antibodies. The amounts of interleukin-8, interferon (IFN)-inducible protein 10 (IP-10), and tumor necrosis factor-α (TNF-α) in the supernatants of cultured neutrophils treated with apoA-I were significantly increased. Combined treatment of neutrophils with IFN-γ and apoA-I produced higher amounts of IP-10 and TNF-α than did treatment with IFN-γ or apoA-I alone. The present study reveals that apoA-I activates neutrophils to produce cytokines and delays spontaneous apoptosis of neutrophils. These findings suggest that apoA-I, although a well-known negative acute-phase protein, has a pro-inflammatory effect in neutrophils.

Serum haptoglobin levels in patients with melancholic and nonmelancholic major depression

Major depression (MD) is accompanied by systemic immune activation or an inflammatory response with the involvement of phagocytic cells, T cell activation, B cell proliferation, and an acute phase response with increased levels of positive and decreased levels of negative acute-phase proteins. In this study, we aimed to determine any differences in serum haptoglobin (Hp) concentrations among patients with melancholic and nonmelancholic MD and the healthy controls. This study involved 125 male patients who were admitted to the Department of Psychiatry, Gulhane Military Medical Academy (GMMA), in Ankara, Turkey. They were diagnosed with MD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and agreed to participate in the study. The melancholic group consisted of 37 patients and the nonmelancholic group had 45 patients. A healthy control group of 40 subjects was selected from the staff of GMMA. These subjects had not had any lifetime psychiatric diagnosis or psychiatric treatment in their medical histories. Peripheral venous blood samples were obtained from the patients and the control group for a complete blood count, routine biochemistry, and the detection of serum Hp levels. There was no statistically significant difference among the melancholic MD, the nonmelancholic MD, and the healthy control groups in terms of age, level of education, and gender. Serum Hp concentrations are significantly higher in melancholic patients as compared with non-melancholic depressed patients and controls. However, there was no statistically significant difference between the nonmelancholic MD and the control group in terms of Hp concentrations. The results of this study are important in terms of showing different serum Hp concentrations in patients with melancholic and nonmelancholic MD.

Connective tissue growth factor reacts as an IL-6/STAT3-regulated hepatic negative acute phase protein.

To investigate the mechanisms involved in a possible modulator role of interleukin (IL)-6 signalling on CYR61-CTGF-NOV (CCN) 2/connective tissue growth factor (CTGF) expression in hepatocytes (PC) and to look for a relation between serum concentrations of these two parameters in patients with acute inflammation. Expression of CCN2/CTGF, p-STAT3, p-Smad3/1 and p-Smad2 was examined in primary freshly isolated rat or cryo-preserved human PC exposed to various stimuli by Western blotting, electrophoretic mobility shift assay (EMSA), reporter-gene-assays and reverse-transcriptase polymerase chain reaction. IL-6 strongly down-regulated CCN2/CTGF protein and mRNA expression in PC, enhanceable by extracellular presence of the soluble IL-6 receptor gp80, and supported by an inverse relation between IL-6 and CCN2/CTGF concentrations in patients' sera. The inhibition of TGFβ1 driven CCN2/CTGF expression by IL-6 did not involve a modulation of Smad2 (and Smad1/3) signalling. However, the STAT3 SH2 domain binding peptide, a selective inhibitor of STAT3 DNA binding activity, counteracted the inhibitory effect of IL-6 on CCN2/CTGF expression much more pronounced than pyrrolidine-dithiocarbamate, an inhibitor primarily of STAT3 phosphorylation. An EMSA confirmed STAT3 binding to the proposed proximal STAT binding site in the CCN2/CTGF promoter. CCN2/CTGF is identified as a hepatocellular negative acute phase protein which is down-regulated by IL-6 via the STAT3 pathway through interaction on the DNA binding level.