Crosstalk among intestinal barrier, gut microbiota and serum metabolome after a polyphenol-rich diet in older subjects with "leaky gut": The MaPLE trial.

BACKGROUND &AIM: The MaPLE study was a randomized, controlled, crossover trial involving adults ≥60 y.o. (n = 51) living in a residential care facility during an 8-week polyphenol-rich (PR)-diet. Results from the MaPLE trial showed that the PR-diet reduced the intestinal permeability (IP) in older adults by inducing changes to gut microbiota (GM). The present work aimed at studying the changes in serum metabolome in the MaPLE trial, as a further necessary step to depict the complex crosstalk between dietary polyphenols, GM, and intestinal barrier. METHODS: Serum metabolome was monitored using a semi-targeted UHPLC-MS/MS analysis. Metataxonomic analysis (16S rRNA gene profiling) of GM was performed on faecal samples. Clinical characteristics and serum levels of the IP marker zonulin were linked to GM and metabolomics data in a multi-omics network. RESULTS: Compared to the control diet, the PR-diet increased serum metabolites related to polyphenols and methylxanthine intake. Theobromine and methylxanthines, derived from cocoa and/or green tea, were positively correlated with butyrate-producing bacteria (the order Clostridiales and the genera Roseburia, Butyricicoccus and Faecalibacterium) and inversely with zonulin. A direct correlation between polyphenol metabolites hydroxyphenylpropionic acid-sulfate, 2-methylpyrogallol-sulfate and catechol-sulfate with Butyricicoccus was also observed, while hydroxyphenylpropionic acid-sulfate and 2-methylpyrogallol-sulfate negatively correlated with Methanobrevibacter. The multi-omics network indicated that participant's age, baseline zonulin levels, and changes in Porphyromonadaceae abundance were the main factors driving the effects of a PR-diet on zonulin. CONCLUSION: Overall, these results reveal the complex relationships among polyphenols consumption, intestinal permeability, and GM composition in older adults, and they may be important when setting personalized dietary interventions for older adults. TRIAL REGISTRATION NUMBER: ISRCTN10214981.

The cortisol response to ACTH in pigs, heritability and influence of corticosteroid-binding globulin.

In the search for biological basis of robustness, this study aimed (i) at the determination of the heritability of the cortisol response to ACTH in juvenile pigs, using restricted maximum likelihood methodology applied to a multiple trait animal model, and (ii) at the study of the relationships between basal and stimulated cortisol levels with corticosteroid-binding globulin (CBG), IGF-I and haptoglobin, all important players in glucose metabolism and production traits. At 6 weeks of age, 298 intact male and female piglets from 30 litters (30 dams and 30 boars) were injected with 250 µg ACTH(1-24) (Synacthen). Blood was taken before ACTH injection to measure basal levels of cortisol, glucose, CBG, IGF-I and haptoglobin, and 60 min later to measure stimulated cortisol levels and glucose. Cortisol increased 2.8-fold after ACTH injection, with a high correlation between basal and stimulated levels (phenotypic correlation, r p=0.539; genetic correlation, r g=0.938). Post-ACTH cortisol levels were highly heritable (h 2=0.684) and could therefore be used for genetic selection of animals with a more reactive hypothalamic-pituitary-adrenocortical axis. CBG binding capacity correlated with cortisol levels measured in basal conditions in males only. No correlation was found between CBG binding capacity and post-ACTH cortisol levels. Basal IGF-I concentration was positively correlated with BW at birth and weaning, and showed a high correlation with CBG binding capacity with a strong sexual dimorphism, the correlation being much higher in males than in females. Basal haptoglobin concentrations were negatively correlated with CBG binding capacity and IGF-I concentrations. Complex relationships were also found between circulating glucose levels and these different variables that have been shown to be related to glucose resistance in humans. These data are therefore valuable for the genetic selection of animals to explore the consequences on production and robustness traits, but also point at pigs as a relevant model to explore the underlying mechanisms of the metabolic syndrome including the contribution of genetic factors.

Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis.

INTRODUCTION: Our objective was to determine the interrelationships of interleukin (IL)-6 receptor inhibition with haemoglobin, acute-phase reactants and iron metabolism markers (including hepcidin) in patients with rheumatoid arthritis (RA). METHODS: Data of patients receiving tocilizumab or placebo in the MEASURE study were analysed. We investigated associations at baseline and during tocilizumab treatment among haemoglobin, parameters of haemoglobin and iron homeostasis [ferritin, total iron-binding capacity (TIBC), hepcidin, haptoglobin], IL-6 and acute-phase reactants [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] to identify statistical correlates of rise in haemoglobin level. RESULTS: At baseline, CRP and haptoglobin were inversely correlated (modestly) with haemoglobin levels. After treatment with tocilizumab, CRP, hepcidin, ferritin and haptoglobin levels fell alongside increases in TIBC and haemoglobin. The falls in CRP, hepcidin and haptoglobin levels in the first 2 weeks correlated with a week 12 rise in TIBC and haemoglobin. CONCLUSIONS: Inflammatory anaemia improves in patients with RA treated with tocilizumab. This improvement correlates with the degree of suppression of systemic inflammation, reduction in hepcidin and haptoglobin and increase in iron-binding capacity. These clinical data provide evidence of a role for IL-6 signalling in the inflammatory anaemia of RA.

Plasma haptoglobin and immunoglobulins as diagnostic indicators of deoxynivalenol intoxication.

This study aimed to discover potential biomarkers for dioxynivalenol (DON) intoxication. B6C3F1 male mice were orally exposed to 0.83, 2.5 and 7.5 mg/kg body weight (bw) DON for 8 days and the differential protein expressions in their blood plasma were determined by SELDI - Time-of-Flight/Mass Spectrometry (TOF/MS) and the immunoglobulins (Igs) G, A, M and E in the serum were investigated. 11.7 kDa protein was significantly highly expressed according to DON administration and this protein was purified by employing a methyl ceramic HyperD F column with using optimization buffer for adsorption and desorption. The purified protein was identified as a haptoglobin precursor by peptide mapping with using LC/Q-TOF/MS and MALDI-TOF/MS and this was confirmed by western blotting and ELISA. IgG and IgM in serum were decreased in a dose-dependent manner and IgA was decreased at 7.5 mg/kg bw DON administration, but the IgE level was not changed. To compare the expressions of haptoglobin and the Igs patterns between aflatoxin B1 (AFB1), zearalenone (ZEA) and DON intoxications, rats were orally administered with AFB1 1.0, ZEA 240 and DON 7.5 mg/kg bw for 8 days. Haptoglobin was increased only at DON 7.5 mg/kg bw, while it was slightly decreased at ZEA 240 mg/kg bw and it was not detected at all at AFB1 1.0 mg/kg bw. IgG and IgA were decreased by DON, but IgG, IgA, IgM and IgE were all increased by AFB1. No changes were observed by ZEA administration. These results show that plasma haptoglobin could be a diagnostic biomarker for DON intoxication when this is combined with examining the serum Igs.

Effects of intramammary infusions of interleukin-8 on milk protein composition and induction of acute-phase protein in cows during mammary involution.

The effects of interleukin-8 (IL-8) on bovine mammary functions such as milk protein secretion and the blood-milk barrier during mammary involution were evaluated. Following the final milking, recombinant bovine (rb) IL-8 (5 or 25 microg) and a saline placebo were individually infused into the left- and right-front teat cisterns of 6 cows, respectively. Three cows without treatment at the final milking were also used as controls. Mammary secretions and blood were collected at -24, 0, 10, 24, 72, 168, 336, and 720 h after infusion. In the mammary glands infused with 25 microg of rbIL-8, the increases in somatic cell counts and in the concentrations of serum albumin, IgG1 and IgG2, and the decreases in the concentrations of alpha- and beta-casein and beta-lactoglobulin were greater than in the control glands. In the mammary glands infused with 5 microg of rbIL-8, compared to the glands infused with 25 microg of rbIL-8, these changes were moderate. These results indicate that rbIL-8 impairs the integrity of the blood-milk barrier and suppresses milk-specific protein secretions. In the cows infused with 25 microg of rbIL-8, the rectal temperature and serum haptoglobin level were transiently elevated after the infusion, showing that intramammary infusion of rbIL-8 could elicit systemic inflammation.

Changes in polymorphonuclear leukocyte elastase concentrations and hemolysis parameters in patients transfused with different blood preparations, and in the blood preparations themselves.

PURPOSE: Massive blood transfusion induces hemolysis and increases polymorphonuclear leukocyte elastase (PMNE) concentration. The purpose of this study was to compare hemolysis and PMNE concentrations in massive blood transfusions with three different preparations. METHODS: In an in vitro study, eight 2-day-old packs of concentrated red blood cells in mannitol, adenine, glucose, phosphate, and citrate solution (MAP-CRC); concentrated red blood cells in citrate, phosphate, and glucose solution (CPD-CRC); or whole blood in citrate, phosphate, and glucose solution (WB) were stored at 4 degrees C. Supernatant concentrations of total and free hemoglobin, total haptoglobin, and PMNE were measured. In an in vivo study, 24 surgical patients with expected bleeding exceeding 3000 ml were transfused with CPD-CRC or MAP-CRC with fresh frozen plasma, or with WB. Platelet count, prothrombin time, activated partial thromboplastin time, serum total and free hemoglobin, and total haptoglobin and plasma PMNE concentrations were measured. RESULTS: In the in vitro study, total and free hemoglobin concentrations were significantly higher in CPD-CRC than in the other two preparations. Total haptoglobin concentration was highest in the order of WB > MAP-CRC > CPD-CRC. The PMNE concentration was significantly higher in WB than in the other two preparations. In the in vivo study, at 3000-ml transfusion, total and free hemoglobin concentrations were significantly lower and activated partial thromboplastin time was longer in the patients with MAP-CRC compared with values in the other two groups. The PMNE concentration was significantly higher in the order of the WB > CPD-CRC > MAP-CRC groups. CONCLUSION: During the storage of MAP-CRC, CPD-CRC, and WB, CPD-CRC had the greatest hemolysis and WB had the highest concentration of PMNE. Patients who received massive blood transfusion of MAP-CRC had the least hemolysis and the lowest concentration of PMNE.

Pharmacogenomics in prevention of diabetic cardiovascular disease: utilization of the haptoglobin genotype in determining benefit from vitamin E.

Numerous large clinical trials have been carried out over the past several years testing the ability of the antioxidant vitamin E to prevent diabetic cardiovascular disease. Meta-analysis of these studies has demonstrated that vitamin E does not provide any cardiovascular protection and may be associated with an increase in mortality. However, these studies did not address possible benefit to subgroups with increased oxidative stress. In this review we provide supporting clinical evidence and a mechanistic basis for utilizing a genetic marker, the haptoglobin genotype, in determining whether vitamin E therapy may or may not be beneficial for a given patient with diabetes.

The influence of a multifunctional, polymeric biomaterial on the concentration of acute phase proteins in an animal model.

The concentrations of the acute phase proteins alpha1-Acid Glycoprotein (AAG) and haptoglobin were determined in Sprague-Dawley-rats after implantation of a novel biodegradable multifunctional polymeric biomaterial for the reconstruction of a gastric wall defect (polymer group; n=42). For comparison, the concentrations of AAG and haptoglobin were measured as well after primary wound closure of the gastric wall defect without biomaterial implantation (control group; n=21) and in rats without any surgical procedure (baseline group; n=21). The implantation periods were 1 week, 4 weeks and 6 months. The concentrations of AAG and haptoglobin were measured by an ELISA assay. Gastrointestinal complications like fistula, perforation or peritonitis did not occur in any of the animals. No statistically significant differences in the concentrations of AAG and haptoglobin were detected between the polymer and the control group. An adequate mechanical stability of the polymeric biomaterial was detectable under the extreme pathophysiological conditions of the stomach milieu. In further examinations the correlation between the intraperitoneal cytokine levels of the animals and the following systemic inflammatory markers should be analysed. Further investigations are needed to analyse the mechanisms of the tissue integration of a biomaterial as well as the process of the tissue remodeling and the influence of the immune system on these mechanisms. The knowledge of these processes is necessary to adapt the multifunctional biomaterial and prepare it thus for the use and implantation in different body locations and to develop novel therapeutical options in medicine.

Application of pharmacogenomics in the prevention of diabetic cardiovascular disease: mechanistic basis and clinical evidence for utilization of the haptoglobin genotype in determining benefit from antioxidant therapy.

Atherosclerotic cardiovascular disease (CVD) and diabetic vascular disease have been associated with an increase in oxidative stress. Mechanistic studies in vitro and in animals have demonstrated a direct role for oxidatively modified protein and lipid molecules in the pathophysiology of these diseases. As a result of this oxidation hypothesis numerous studies have been carried out over the past 5-10 years testing the ability of antioxidant vitamins to decrease the incidence of these diseases. The general consensus from these studies, involving over 200,000 individuals, has been that antioxidant vitamins do not provide any vascular protection. Moreover, several of these studies have demonstrated that antioxidant supplementation may be associated with an increased incidence of disease and mortality. One reason why these antioxidant vitamins may have failed to demonstrate benefit may have been due to inappropriate patient selection. In this review we provide supporting clinical evidence and a mechanistic basis for utilizing a genetic marker, the haptoglobin (Hp) genotype, in determining whether antioxidant vitamin therapy may or may not be beneficial for a given patient with diabetes.

The acute-phase response of the liver in relation to thyroid hormone-induced redox signaling.

Recently, we reported that 3,3',5-triiodothyronine (T3) induces the expression of redox-sensitive genes as a nongenomic mechanism of T3 action. In this study, we show that T3 administration to rats (daily doses of 0.1 mg/kg ip for 3 consecutive days) induced a calorigenic response and liver glutathione depletion as an indication of oxidative stress, with higher levels of interleukin (IL)-6 in serum (ELISA) and hepatic STAT3 DNA binding (EMSA), which were maximal at 48-72 h after treatment. Under these conditions, the protein expression of the acute-phase proteins haptoglobin and beta-fibrinogen is significantly augmented, a change that is suppressed by pretreatment with alpha-tocopherol (100 mg/kg ip) or gadolinium chloride (10 mg/kg iv) before T3. It is concluded that T3 administration induces the acute-phase response in rat liver by a redox mechanism triggered at the Kupffer cell level, in association with IL-6 release and activation of the STAT3 cascade, a response that may contribute to reestablishing homeostasis in the liver and extrahepatic tissues exhibiting oxidative stress.

The impact of controlled release capsules of monensin on postcalving haptoglobin concentrations in dairy cattle.

This study was designed to assess the impact of a controlled release capsule (CRC) of monensin, administered prior to calving, on postcalving haptoglobin levels. The role of disease on haptoglobin levels was also studied. The study population consisted of 1010 cows from 25 Holstein dairy herds near Guelph, Ontario. Monensin CRC or placebo capsules were randomly assigned within each herd 3 wk prior to the expected calving date. Serum from week 1 and week 6 postcalving was submitted for quantification of haptoglobin concentrations. Haptoglobin results were analyzed for associations with treatment, health data, and individual cow factors up to 95 d in milk. Haptoglobin concentrations were higher in week 1 than week 6 (P < 0.05). In univariate analysis, several diseases were significantly associated with haptoglobin concentrations. However, occurrence of disease appeared to be a confounding factor in the data interpretation. Thus, the analysis was stratified by the presence or absence of disease. There appeared to be associations between factors other than clinical disease contributing to increased haptoglobin levels in both clinically healthy and unhealthy cattle. Haptoglobin served as a good indicator of inflammatory disease. Monensin CRC treatment was associated with increased haptoglobin concentrations in clinically unhealthy cattle, perhaps reflecting a better ability to respond to disease challenge. The lower haptoglobin concentrations in monensin CRC treated cattle that were clinically normal may be a reflection of reduced subclinical disease.

Influence of hormone replacement therapy on proteomic pattern in serum of postmenopausal women.

OBJECTIVES: Proteomics approaches to cardiovascular biology and disease hold the promise of identifying specific proteins and peptides or modification thereof to assist in the identification of novel biomarkers. METHOD: By using surface-enhanced laser desorption and ionization time of flight mass spectroscopy (SELDI-TOF-MS) serum peptide and protein patterns were detected enabling to discriminate between postmenopausal women with and without hormone replacement therapy (HRT). RESULTS: Serum of 13 HRT and 27 control subjects was analyzed and 42 peptides and proteins could be tentatively identified based on their molecular weight and binding characteristics on the chip surface. By using decision tree-based Biomarker Patternstrade mark Software classification and regression analysis a discriminatory function was developed allowing to distinguish between HRT women and controls correctly and, thus, yielding a sensitivity of 100% and a specificity of 100%. The results show that peptide and protein patterns have the potential to deliver novel biomarkers as well as pinpointing targets for improved treatment. The biomarkers obtained represent a promising tool to discriminate between HRT users and non-users. CONCLUSION: According to a tentative identification of the markers by their molecular weight and binding characteristics, most of them appear to be part of the inflammation induced acute-phase response.

Serum acute phase protein concentrations after hysterectomy with and without low-molecular-weight heparin thrombosis prophylaxis.

Background. Low-molecular-weight heparin (LMWH) is recommended for venous thrombosis prophylaxis. There are several lines of evidence that heparins exhibit anti-inflammatory properties in addition to their anticoagulant activity. Therefore, we decided to estimate the concentrations of C-reactive protein (CRP) and haptoglobin, as acute-phase proteins, in the blood serum of patients who underwent total abdominal hysterectomy with and without the LMWH administration. Method. Forty-two women were studied, including 26 patients treated with enoxaparin and a group of 16 women without thrombosis prophylaxis. Haptoglobin and CRP concentrations were measured in serum samples obtained before the operation and also 8, 24, 48, 72, 96, and 192 hr after surgery. Results. Serum CRP level measured 8 hr after the operation was significantly higher in the group without thrombosis prophylaxis, however, no statistically significant differences in the concentration of CRP between studied groups in the other time periods were found. There were no statistically significant differences in serum haptoglobin levels between the groups of patients in all time periods. Conclusion. Administration of low-molecular-weight heparin may affect CRP production, however, further studies are still needed in order to clarify the exact immunosuppressive action of heparins.

Effects of heparin administration on Trypanosoma brucei gambiense infection in rats.

We examined whether heparin administration influences in vivo trypanosome proliferation in infected rats. Administration of heparin every 8 hr via cardiac catheter inhibited growth of Trypanosoma brucei gambiense and prolonged survival of treated rats. Heparin administration increased lipoprotein lipase activity, high-density lipoprotein (HDL) concentration in the blood, and haptoglobin messenger RNA content of the liver. The presence of heparin in culture media did not directly affect proliferation of trypanosomes in vitro. However, the addition of plasma from infected rats treated with heparin to culture media decreased the number of trypanosomes. This effect was decreased by incubating the trypanosomes with benzyl alcohol, a known inhibitor of receptor-mediated endocytosis of lipoprotein. These data suggested that heparin administration reduced the number of trypanosomes in infected rats. Trypanosome lytic factor, a HDL and haptoglobin-related protein, protects humans and some animals from infection by Trypanosoma brucei brucei. In rats, increases in HDL and haptoglobin may affect the proliferation of T. b. gambiense.

Effect of K, MG aspartate on some biological parameters of aging rats.

The effect of K and Mg salts of aspartic acid (Cardilan) on the serum concentration of selected proteins and phagocytic activity in aging male Wistar rats was investigated. Cardilan was administered in tap water for 7 days a month for 3 months before the last observed interval (12, 18 and 24 month). In a part of animals, the aging process was accelerated by sublethally gamma-irradiation. The administration of Cardilan slowed down the changes in the concentration of prealbumin, albumin, haptoglobin, haemopexin, C3 complement in non-irradiated rats (DC). This effect was extended to the changes in transferrin level in irradiated rats (IDC). The phagocytic activity in both DC, IDC rats was lower compared with controls drinking water (DW, IDW), but not significantly. The effect of Cardilan administration appears to be the greatest in 24-month-old rats, when the treated animals survived better by 25% in IDC group and by 26% better in DC rats, compared with those of the same age controls. Potassium and magnesium salts of aspartates are suitable compounds for life prolongation in the experimental conditions.

Biomarker responses in river otters experimentally exposed to oil contamination.

Investigations in Prince William Sound (Alaska, USA) following the Exxon Valdez oil spill (EVOS) revealed that river otters (Lontra canadensis) on oiled shores had lower body mass and elevated values of biomarkers, than did otters living on nonoiled shores. In addition, otters from oiled areas selected different habitats, had larger home ranges, and less diverse diets than animals living in nonoiled areas. These differences between river otters from oiled shores and those from nonoiled areas strongly suggested that oil contamination had an effect on physiological and behavioral responses of otters. In this study, we explored the effects of crude oil contamination on river otters experimentally. We hypothesized that exposure to oil would result in elevated values of biomarkers, indicating induced physiological stress. Fifteen wild-caught male river otters were exposed to two levels of weathered crude oil (i.e., control, 5 ppm/day/kg body mass, and 50 ppm/day/kg body mass) under controlled conditions in captivity at the Alaska Sealife Center in Seward (Alaska, USA). Responses of captive river otters to oil ingestion provided mixed results in relation to our hypotheses. Although hemoglobin (Hb, and associated red blood cells) and white blood cells, and possibly interleukin-6 immunoreactive responded in the expected manner, other parameters did not. Aspartate aminotransferase, alanine aminotransferase, and haptoglobin (Hp), did not increase in response to oiling or decreased during rehabilitation. Conversely, principle-component analysis identified values of alkaline phosphatase as responding to oil ingestion in river otters. Our results suggested that opposing processes were concurring in the oiled otters. Elevated production of Hp in response to tissue damage by hydrocarbons likely occurred at the same time with increased removal of Hp-Hb complex from the serum, producing an undetermined pattern in the secretion of Hp. Thus, the use of individual biomarkers as indicators of exposure to pollutants may lead to erroneous conclusions because interactions in vivo can be complicated and act in opposite directions. Additionally, the biomarkers used in investigating effects of oiling on live animals usually are related to the heme molecule. Because of the opposing processes that may occur within an animal, data from a suite of heme-related biomarkers may produce results that are difficult to interpret. Therefore, we advocate the exploration and development of other biomarkers that will be independent from the heme cycle and provide additional information to the effect of oiling on live mammals.

Effect of intramammary infusion of tumour necrosis factor-alpha on milk protein composition and induction of acute-phase protein in the lactating cow.

The present study was designed to evaluate the effects of tumour necrosis factor-alpha (TNF-alpha) on lactating bovine mammary functions such as milk protein secretion and the integrity of the milk-blood barrier. The effect on the induction of the systemic inflammatory response was also examined using concentrations of serum haptoglobin (Hp), a major inflammatory acute-phase protein, as an index. One hundred micrograms per mammary gland of recombinant bovine (rBo) TNF-alpha or placebo saline was individually infused into a rear mammary gland of each of four lactating cows, and milk and blood samples were collected before and 4, 8, 24, 32, 48, 96 and 168 h after infusion. In the rBoTNF-alpha-infused gland, increases of somatic cell counts were observed at 4-48 h. Although concentrations of total milk protein were not changed, compositions of milk proteins varied following rBoTNF-alpha infusion. Concentrations of caseins, alpha-lactalbumin and beta-lactoglobulin were significantly decreased at 4 and 8 h. Lactoferrin concentrations were significantly increased at 4 h. Significant infiltrations of serum albumin, immunoglobulin G1 (IgG1) and IgG2 were observed at 4 and 8 h. Elevations of the serum concentration of Hp were detected at 8-32 h, but were very small in comparison with those reported in inflammatory diseases. Changes in rectal temperature and white blood cell counts were not significant. These results show that single rBoTNF-alpha infusion into the lactating mammary gland suppresses the lactogenic function of the gland and influences the function of the milk-blood barrier, with little effect on the generalized inflammatory response.

Activation of cellular responses to interleukin 6 is blocked by staurosporine.

Interleukin 6 (IL-6) acts on a wide spectrum of cells and can regulate differentiation or growth in these different cells. The effects of the microbial alkaloid staurosporine (SS) on IL-6 signaling through gp130, and also on the internalization of the IL-6 receptor complex, were studied using HepG2 cells which are well-characterized in their ability to respond to IL-6 by upregulating acute-phase protein production. SS was found effective in the blockade of the signaling cascade of IL-6: phosphorylation of both gp130 and Stat3 was eliminated by SS treatment and the production of IL-6 stimulated haptoglobin by the cells was abolished. In addition, SS reduced the internalization rate of 125I-IL-6 by 50%, resulting in a retention of 125I-IL-6 on the cell surface and a corresponding decrease in degraded 125I-IL-6 in the extracellular medium. SS is commonly employed as an apoptosis inducing agent but the mechanism of its action is not clear. The ability of SS to void the capacity of IL-6, and IL-6-related cytokines such as Oncostatin M, to deliver growth and differentiation signals may be one process by which this agent could promote apoptosis in a variety of cell types.

Tissue, temporal and inducible expression pattern of haptoglobin in mice.

Haptoglobin (Hp) is a member of the acute phase plasma proteins previously thought to be synthesized solely by the adult liver. The present study analyzes the tissue and temporal expression pattern of endogenous haptoglobin in the mouse and acute phase inducibility in various tissues. The liver is found to be the major site of haptoglobin expression but significant expression levels were also observed in the lung and skin. Acute phase induction by bacterial lipopolysaccharide (LPS) demonstrated that haptoglobin was induced not only in the liver but also in other tissues, including lung, skin, spleen, and kidney. Temporal analyses demonstrated that haptoglobin is expressed during embryogenesis in the liver and is inducible in various tissues surveyed throughout development. Transgenic mice that harbored a 1.05-kilobase (kb) region of the human haptoglobin promoter linked to two different reporter genes gave rise to lung-specific expression in the majority of transgenic lines with minimal liver expression. However, when induced with lipopolysaccharide, the 1.05-kb fragment contained the necessary elements for a response comparable to endogenous expression levels. In conclusion, these studies demonstrate that haptoglobin is not an adult liver specific gene, and its role as an acute phase reactant may well be more diverse than previously suspected.