Acute Phase Proteins In Liver Research Articles

Acute phase response to exertional heat stroke in mice.

What is the central question of this study? Exertional heat stroke is accompanied by a marked inflammatory response. In this study, we explored the time course of acute phase proteins during recovery from severe heat stress in mice and the potential role of skeletal muscles as their source. What is the main finding and its importance? Exertional heat stroke transiently increased expression of acute phase proteins in mouse liver and plasma and depleted liver and plasma fibrinogen, a typical response to severe trauma. In contrast, skeletal muscle fibrinogen production was stimulated by heat stroke, which can provide an additional reservoir for fibrinogen supply to maintain the clotting potential throughout the body and locally within the muscle. Exertional heat stroke (EHS), the most severe manifestation of heat illness, is accompanied by a marked inflammatory response. The release of acute phase proteins (APPs) is an important component of inflammation, which can assist in tissue survival/repair. The time course of APPs in recovery from EHS is unknown. Furthermore, skeletal muscles produce APPs during infection, but it is unknown whether they can produce APPs after EHS. Our objective was to determine the time course of representative APPs in liver, plasma and skeletal muscle during recovery from EHS. Male C57BL6/J mice ran in a forced running wheel at 37.5°C, 40% relative humidity until symptom limitation. Exercise control (EXC) mice ran for the same duration and intensity at 22.5°C. Samples were collected (n=6-12 per group) over 14days of recovery. Protein abundance was quantified using immunoblots. Total and phosphorylated STAT3 (pSTAT3) at Tyr705, responsible for APP activation, increased in liver at 0.5h after EHS compared with EXC, (P<0.05 and P<0.001, respectively). In contrast, in tibialis anterior (TA) muscle, total STAT3 increased at 3h (P<0.05) but pSTAT3 (Tyr705) did not. Liver serum amyloidA1 (SAA1) increased at 3 and 24h after EHS (P<0.05), whereas plasma SAA1 increased only at 3h (P<0.05). SAA1 was not detected in TA muscle. In liver and plasma, fibrinogen decreased at 3h (P<0.01) and increased in TA muscle (P<0.05). Lipocalin-2 was undetectable in liver or TA muscle. Recovery from EHS is characterized by a transient acute phase response in both liver and skeletal muscle. However, APP expression profiles and subtypes differ between skeletal muscle and liver.

A 12-wk whole-grain wheat intervention protects against hepatic fat: the Graandioos study, a randomized trial in overweight subjects

Whole-grain wheat (WGW) is described as nutritionally superior to refined wheat (RW) and thus advocated as the healthy choice, although evidence from intervention studies is often inconsistent. The liver, as the central organ in energy metabolism, might be an important target organ for WGW interventions. The aim of this study was to investigate the potential benefits of WGW consumption compared with RW consumption on liver health and associated parameters. We performed a double-blind, parallel trial in which 50 overweight 45- to 70-y-old men and postmenopausal women were randomly allocated to a 12-wk intervention with either WGW (98 g/d) or RW (98 g/d) products. Before and after the intervention we assessed intrahepatic triglycerides (IHTGs) and fat distribution by proton magnetic resonance spectroscopy/magnetic resonance imaging, fecal microbiota composition, adipose tissue gene expression, and several fasting plasma parameters, as well as postprandial plasma lipids after a mixed meal. Fasting plasma cholesterol, triglycerides, nonesterified fatty acids, and insulin were not affected by RW or WGW intervention. We observed a substantial increase of 49.1% in IHTGs in the RW when compared with the WGW group (P=0.033). Baseline microbiota composition could not predict the increase in IHTGs after RW, but gut microbiota diversity decreased in the RW group when compared with the WGW group (P=0.010). In the WGW group, we observed increased postprandial triglyceride levels compared with the RW group (P=0.020). In addition, the WGW intervention resulted in a trend towards lower fasting levels of the liver acute-phase proteins serum amyloid A (P=0.057) and C-reactive protein (P=0.064) when compared to the RW intervention. A 12-wk RW intervention increases liver fat and might contribute to the development of nonalcoholic fatty liver disease, whereas a 12-wk 98-g/d WGW intervention prevents a substantial increase in liver fat. Our results show that incorporating feasible doses of WGW in the diet at the expense of RW maintains liver health. The study was registered at clinicaltrials.gov as NCT02385149.

Investigation of the Effect of Tarantula cubensis Extract on Acute Phase Response

Background: Tarantula cubensis alcoholic extract is used to accelerate wound healing and to relieve edema in many animal species. In addition, it may be useful for many infectious diseases. Considering to these effects, it is believe that these effects may be on immune system. Cytokines (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10 and interferon gamma) secreted by immune cells and acute phase proteins (haptoglobin, alpha 1 acid glycoprotein, serum amyloid A) secreted by liver play role in acute phase response. The aim of the present study was to determine the effect of Tarantula cubensis alcoholic extract on cytokine and acute phase protein levels in sheep.Materials, Methods &amp; Results: Tarantula cubensis alcoholic extract (6 mL/sheep, subcutaneously, single dose) was administered to 6 healthy sheep. Blood samples were obtained before (0 h) and after treatments at 2, 4, 8, 12, 24 and 48 h. Then, blood samples were centrifuged to obtain serum samples. Acute phase cytokines such as serum tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10, interferon gamma and acute phase proteins such as haptoglobin, alpha 1 acid glycoprotein and serum amyloid-A concentrations were determined with commercially available kits on ELISA reader. Administration of Tarantula cubensis alcoholic extract caused fluctuations in tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10, interferon gamma levels in sheep. In addition, levels of haptoglobin, alpha 1 acid glycoprotein, serum amyloid A showed fluctuations. But, these fluctuations in acute phase cytokines and acute phase proteins were not statistically significant (P &gt; 0.05).Discussion: Tarantula cubensis alcoholic extract, homeopathic medicine, is used trauma, retentio secundinarium, tendinitis, bluetongue, foot and mouth, metritis and arthritis in many animal species including sheep. Cytokines, secreted against various stimulus including infectious diseases, play role in wound healing and in the regulation of the immune system. In current study, administration of Tarantula cubensis alcoholic extract lead to fluctuations in tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10 and interferon gamma levels, but these changes were not statistically significant (P &gt; 0.05). Non-statistical fluctuations in cytokines result from inadequate immunological response of sheep against to Tarantula cubensis alcoholic extract. Also, use of molecular analysis techniques may be changed these results. Acute phase proteins are significantly secreted from the liver during the acute phase response. In current study, administration of Tarantula cubensis alcoholic extract in sheep caused non-statistifical fluctuations on haptoglobin, alpha 1 acid glycoprotein and serum amyloid A levels (P &gt; 0.05). Tumor necrosis factor alpha and interleukin-1 beta stimulate synthesis of interleukin-6. Interleukin-6 provides synthesis of acute phase proteins in liver. Non-statistical fluctuations in acute phase proteins result from inadequate stimulus of IL-6. In conclusion, it may be stated that administration of Tarantula cubensis alcoholic extract has no distinctive effect on the acute phase response. However, when Tarantula cubensis alcoholic extract is administered repeated times or other acute phase parameters are evaluated, different results may be observed.

On the Non-Redundant Roles of TDO2 and IDO1.

The Perspective by Pallotta et al. (1) offers the opportunity of a few more considerations on the mutually supportive relationship between tryptophan catabolic enzymes and the aryl hydrocarbon receptor (AhR) in the transitional response aimed at reinstalling homeostatic tolerance after meeting the needs of an acute inflammatory reaction (2). One major question is in fact – Why does AhR need two distinct sources of the ligand kynurenine to become activated, namely, tryptophan 2,3-dioxygenase (TDO2) and indoleamine 2,3-dioxygenase (IDO1) (3)? (The third known tryptophan catabolic enzyme, IDO2, has limited catalytic activity relative to the two others.). The IDO1–AhR axis would, in fact, appear to be a highly efficient mechanism per se, in that it acts in a feedforward loop [i.e., kynurenine is an activating ligand for AhR, and activated AhR promotes Ido1 transcription (4)], and it is self-regulated [AhR presides over regulatory proteolysis of IDO1, to restore homeostasis, as proposed by Pallotta et al. (1)]. For this loop to be operative, one need must be absolutely met, namely, the absence of IL-6, which operates its own mode of IDO1 proteasomal degradation via induction of SOCS3, resulting in the enzyme ubiquitination and proteolysis (5). Although it is one of AhR’s multiple jobs to transcriptionally repress Il6 – through transcription of Il10 (6) – the AhR–IDO1 system is IL-6-sensitive, and the “early” kynurenine leading to the recruitment of IL-10 to the transitional response must derive from a source other than the IDO1–AhR axis, that is, an enzyme not amenable to suppression by IL-6. At the onset of an inflammatory response, IL-6 production is a necessary, defensive mechanism that need not be abrogated till the onset of the transition that will contribute to reinstall an optimal balance between inflammation and tolerance. Among the early events of systemic inflammation is cortisol-driven induction of acute phase proteins in liver. TDO2 is one such protein, and it is synthesized when production of proinflammatory cytokines, including IL-6, is at its height. Tdo2 is not under AhR transcriptional control, nor is TDO2 amenable to IL-6-driven proteasomal degradation (3). This makes TDO2 production of kynurenine – and AhR activation – compatible with the events initiating the transitional response (Figure ​(Figure11). Figure 1 Sequential events marking the transitional response aimed at reinstalling homeostatic tolerance after meeting the needs of an acute inflammatory reaction, with TDO2 and IDO1 having temporally segregated roles. The conclusion is that the roles of TDO2 and IDO1 as a source of AhR ligands are not redundant, the major differences lying in the different modalities of their respective gene activation, their being temporally segregated in function, and their disparate susceptibilities to inhibition by IL-6.

Abstract 4900: The role of Interleukin (IL)-22 on the UVB-induced proliferation and inflammation of human keratinocyte cell line, HaCaT

Abstract Interleukin 22 (IL-22), a member of IL-10 family, is a potent mediator of inflammatory responses. It is produced by activated CD4+ T cells and natural killer (NK) cells, but IL-22Rα expression is restricted to nonhematopoietic cells in the skin, pancreas, intestine, liver, lung and kidney. IL-22 suppresses IL-4 production from Th2 cells and induces acute phase proteins in liver and pancreas. It is recently found that IL-22 plays a critical role in the maintenance of epidermal homeostasis by controlling cell cycle of keratinocytes. Therefore, we investigated that role of IL-22 on the proliferation and inflammation of ultraviolet B (UVB)-irradiated human keratinocytes, HaCaT. First, we found the expression of IL-22Rα mRNA and protein level was increased in HaCaT by UVB (100 J/m2) irradiation. Interestingly, the translocation of IL-22Rα from cytosol to membrane was increased by UVB irradiation. When UVB-irradiated HaCaT was cultured in the presence of recombinant IL-22 (rIL-22), the suppressed proliferation of HaCaT by UVB was rescued. In addition, we found that the production of UVB-induced pro-inflammatory cytokines, such as IL-1α, IL-6 and IL-18, was increased by the treatment of rIL-22. Taken together, IL-22 plays a critical role in inflammation by UVB irradiation. And it suggests that UVB-induced skin inflammation could effectively be controlled by the regulation of IL-22 production and its action on keratinocytes. Note: This abstract was not presented at the meeting. Citation Format: Yejin Kim, Hyemin Kim, Jiwon Choi, Mirim Jang, Jiyea Choi, Jae Seung Kang, Wang Jae Lee. The role of Interleukin (IL)-22 on the UVB-induced proliferation and inflammation of human keratinocyte cell line, HaCaT. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4900. doi:10.1158/1538-7445.AM2014-4900

Hyperglycemia Exacerbates Burn-Induced Liver Inflammation via Noncanonical Nuclear Factor-κB Pathway Activation

Hyperglycemia and inflammation are hallmarks of burn injury. In this study, we used a rat model of hyperglycemia and burn injury to investigate the effects of hyperglycemia on inflammatory responses in the liver. Hyperglycemia was induced in male Sprague-Dawley rats with streptozotocin (STZ) (35-40 mg/kg), followed by a 60% third-degree scald burn injury. Cytokine levels (by multiplex, in cytosolic liver extracts), hormones (by enzyme-linked immunosorbent assay [ELISA], in serum), nuclear factor (NF)-κB protein deoxyribonucleic acid (DNA) binding (by ELISA, in nuclear liver extracts) and liver functional panel (using VetScan, in serum) were measured at different time points up to 7 d after burn injury. Blood glucose significantly increased after burn injury in both groups with different temporal patterns. Hyperglycemic rats were capable of endogenous insulin secretion, which was enhanced significantly versus controls 12 h after burn injury. DNA binding data of liver nuclear extracts showed a robust and significant activation of the noncanonical NF-κB pathway in the hyperglycemic versus control burn animals, including increased NF-κB-inducing kinase expression (p < 0.05). Liver acute-phase proteins and cytokine expression were increased, whereas secretion of constitutive proteins was decreased after burn injury in hyperglycemic versus control animals (p < 0.05). These results indicate that burn injury to the skin rapidly activated canonical and noncanonical NF-κB pathways in the liver. Robust activation of the NF-κB noncanonical pathway was associated with increased expression of inflammatory markers and acute-phase proteins, and impaired glucose metabolism. Hyperglycemia is detrimental to burn outcome by augmenting inflammation mediated by hepatic noncanonical NF-κB pathway activation.

The role of interleukin (IL)-22 on the proliferation of human keratinocyte cell line, HaCaT by Ultraviolet B (UVB) irradiation (44.27)

Abstract Interleukin 22 (IL-22), a member of IL-10 family, is a potent mediator of inflammatory responses. It is produced by activated CD4+ T cells and natural killer (NK) cells, but its receptor expression is restricted to nonhematopoietic cells in the skin, pancreas, intestine, liver, lung and kidney. IL-22 suppresses IL-4 production from Th2 cells and induces acute phase proteins in liver and pancreas. It is recently found that IL-22 plays a critical role in the maintenance of epidermal homeostasis by controlling cell cycle of keratinocytes. Therefore, we investigated that role of IL-22 on the proliferation of UVB-irradiated human keratinocytes, HaCaT. First, we found the increase of IL-22 mRNA expression was increased in HaCaT by UVB irradiation (150J/m2). When UVB-irradiated HaCaT was cultured in the presence of recombinant IL-22, the suppressed proliferation of HaCaT by UVB was rescued. It was closely related with the progression of cell cycle in UVB-irradiated HaCaT. We confirmed that the hyperproliferation and cell cycle progression of UVB-irradiated HaCaT by the addition of activated T cells or its culture supernatant. Taken together, IL-22 plays a critical role in the deterioration of epidermal hyperplasia by UVB irradiation. And it suggests that UVB-induced skin inflammation could effectively be controlled by the regulation of IL-22 production and its action on keratinocytes.

Effect of chronic ethanol consumption on the expression of complement components and acute-phase proteins in liver

The complement system can provoke but also participate in the repair of liver injury. Here we investigated by microarray analysis the effect of chronic ethanol consumption on hepatic mRNA expression of complement components and acute-phase proteins in complement C3-deficient ( C3 −/−) and wild-type ( C3 +/+) mice. Up-regulation by ethanol of factor B, C1qA-chain and clusterin but down-regulation of factor H, Masp-2, factor D and the terminal components C6, C8α and C9 was seen in both strains. Ethanol up-regulated C2 and down-regulated C4bp only in C3 +/+ mice, while in C3 − /− mice up-regulation of C1qB-chain and vitronectin was observed. The expression of factor B, C6, C1qB and factor I was lower but that of factor D higher in C3 − /− than in C3 +/+ mice. Ethanol induced mRNA synthesis of many acute-phase proteins including SPARC and lipocalin-2, but reduced the expression of SAP. The induction of early classical and alternative pathway components and suppression of terminal pathway components and soluble regulators may thus contribute to alcohol-induced liver injury. Lipocalin-2 and SPARC emerge as new candidate markers for early detection of liver damage.

Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1β in hepatocytes

Interleukin-1beta (IL-1beta) is a major inducer of liver acute-phase protein expression in response to infection. Several transcription factors, including CCAAT/enhancer binding protein (C/EBP), are known mediators in this process, although the mechanisms by which they modulate IL-1beta's action are not completely understood. Activation of sphingomyelinase (SMase) and the subsequent generation of ceramide are early steps in the IL-1beta signaling cascade. In this study, we investigate the role of ceramide in the IL-1beta regulation of C/EBP in primary hepatocytes. The C/EBP DNA binding activity was found to increase in a dose-dependent manner after stimulation with IL-1beta and exogenous addition of C2-ceramide or treatment with SMase. These changes were accompanied by an increase in the nuclear content of C/EBPbeta. Both IL-1beta and ceramide led to extracellular signal-regulated kinase 1/2 (ERK1/2) activation as early as 15 min after treatment. Furthermore, the increase of cellular ceramide content resulted in increased phosphorylation of C/EBPbeta at serine 105 at later time points. Concurrently, the cytosolic levels of C/EBPbeta decreased, suggesting that IL-1beta and ceramide induced nuclear translocation of C/EBPbeta. Ceramide-induced C/EBPbeta phosphorylation, translocation, and DNA binding were suppressed by the addition of PD98059, an inhibitor of ERK1/2 phosphorylation. These results suggest that ceramide and ERK mediate a pathway in the IL-1beta signaling cascade, which results in rapid posttranslational activation of C/EBPbeta.

Metabolic effects of host defence responses during gastrointestinal parasitism in sheep

Following stimulation of the immune system, tissue trauma, or exposure to some stressors, there can be activation of the acute phase response (APR). This is a primitive defence reaction that helps protect the host against noxious insults. Part of the response involvess a change in priorities for nutrient utilisation, when the pro-inflammatory cytokines IL-1α/β, TNFα, IL-6 and IFNα/β override the normal hypothalamic-somatotropic control of nutrient utilisation. The pro-inflammatory cytokines reduce protein synthesis and increase protein catabolism in muscle, induce synthesis of acute phase proteins in liver, and decrease de novo fatty acid synthesis and increase lipolysis in adipose tissue. In the central nervous system there is induction of fever, which increases metabolic rate, and induction of sickness behaviour. There are few reports in the literature of studies on the APR during gastrointestinal nematode (GIN) infection in sheep. However, IL-6 message is present in mucosa during Trichostrongylus colubriformis infection and mast cells in many species contain preformed TNFα. The changes in appetite, growth and nitrogen metabolism seen during GIN parasitism in sheep are in accord with the systemic effects of the APR. This review reports studies on activation of the APR in mastitis and fly strike, and the effects of APR on wool growth in high and low tensile strength genotypes and during Haemonchus contortus infection. The modified capacity of tissues to take up amino acids during pro-inflammatory cytokine perturbation of nutrient utilisation may limit the capacity for dietary supplementation to remedy the cost of host defence. Genetic variation may occur in production of pro-inflammatory cytokines or in tissue sensitivity to pro-inflammatory cytokines during GIN infection and may provide a basis for selection for resilience. Some questions for future research are identified.

Central injection of nitric oxide synthase inhibitors increases peripheral interleukin-6 and serum amyloid A: involvement of adrenaline from adrenal medulla.

1. Accumulating evidence suggests that plasma levels of interleukin-6 (IL-6), a major cytokine stimulating the synthesis of acute phase proteins, are intimately regulated by the central nervous system (CNS). 2. In the present study, effects of intracerebroventricular (i.c. v) injection of N(G)-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole, nitric oxide synthase (NOS) inhibitors, on plasma IL-6 levels and peripheral IL-6 mRNA expression were examined in mice. 3. L-NAME (0.1 - 2 microg per mouse i.c.v.) and 7-nitroindazole (0.2 - 2 microg per mouse i.c.v.) induced a dose-dependent increase in plasma IL-6 levels and a subsequent increase in circulating serum amyloid A, a liver acute-phase protein. In contrast, an intraperitoneal (i.p.) injection of L-NAME up to the dose of 25 microg per mouse had no effect. 4. Pretreatment with yohimbine (alpha(2)-adrenergic antagonist; 1 mg kg(-1) i.p.), or ICI-118,551 (beta(2)-adrenergic antagonist; 2 mg kg(-1) i.p.), but not with prazosin (alpha(1)-adrenergic antagonist; 1 mg kg(-1) i.p.), nor betaxolol (beta(1)-adrenergic antagonist; 2 mg kg(-1) i.p.), significantly inhibited the central L-NAME-induced plasma IL-6 levels. 5. I.c.v. (50 microg per mouse) or i.p. (100 mg kg(-1)) pretreatment with 6-hydroxydopamine had no effect on central L-NAME-induced plasma IL-6 levels. However, intrathecal (i.t.) pretreatment with 6-hydroxydopamine (20 microg per mouse) markedly inhibited central L-NAME-induced plasma IL-6 levels. Both yohimbine (1.5 microg per mouse i.t.) and ICI-118,551 (1.5 microg per mouse i. t.) were effective in inhibition of central L-NAME-induced plasma IL-6 levels. 6. There was an elevation of base-line plasma IL-6 levels in adrenalectomized animals. The adrenalectomy-enhanced levels were not further increased by central L-NAME. 7. L-NAME (2 microg per mouse i.c.v.) induced an increase in IL-6 mRNA expression in liver, spleen, and lymph node. 8. These results suggest that NOS activity in the brain tonically down-regulates peripheral IL-6 by inhibiting adrenaline release from the adrenal medulla.

Acute Exposure to CNTFin VivoInduces Multiple Components of Reactive Gliosis

CNS trauma or disease induces a constellation of changes in the glia comprising the condition known as reactive gliosis. At present, little is known regarding the nature of the injury signals and the specific consequences of their actions. Ciliary neurotrophic factor (CNTF) induces acute phase proteins in liver and increases astrocytic glial fibrillary acidic protein (GFAP) bothin vitroandin vivo.The purpose of the present study was to establish whether CNTF induces other aspects of gliosis. Between 10 and 72 h after 100 ng of recombinant human CNTF was administered into the adult rat neocortex, alterations were observed in a region extending several millimeters in circumference from the injection site. Microglia in this region were more apparent and astrocytes were hypertrophic. Byin situhybridization, mRNAs for GFAP, vimentin, and clusterin were upregulated when compared to the control hemisphere (which received heat-inactivated CNTF). By immunocytochemistry, GFAP, vimentin, glutathione-S-transferase μ, S-100, and OX-42 were elevated by 48 h. By contrast, the oligodendroglial marker GST Yp, the neuronal markers MAP-2 and NSE, the intermediate filament nestin, and the stress protein αB-crystallin were unchanged. In addition, a greater than twofold increase in the number of proliferating cells was observed. Since CNTF induces swelling and multiple “gliotic” genes in astrocytes, increases microglial number, and stimulates cell proliferation, we conclude that CNTF is sufficient to induce multiple aspects of gliosis. These data are consistent with a model whereby CNTF (which is synthesized by astrocytes) would be released when the integrity of the astrocyte membrane is compromised, whereupon it would elicit an inflammatory response.

The expression of liver acute-phase protein genes during rat development and in response to inflammation of the dam

Abstract The hepatic expression of albumin (Al) and plasma acute phase protein genes (APP) was examined during the development of rat liver and in response to inflammation of the dam. Throughout the 10- to 20-day gestation period the level of α 2-macroglobulin (α2M) mRNA in fetal liver exceeded twice that of the adult liver. The concentrations of the other APP and Al mRNAs were 10–30% of those of the adult liver between days 10 and 13 of gestation, then increased to values which ranged from 40% for haptoglobin (Hp) to 80% for Al and α 1-acid glycoprotein (AGP) mRNAs on day 19 of gestation. The transition of fetuses to an extrauterine environment was followed by a temporary overexpression of the Hp gene and an increase of the fibrinogen (Fb), AGP and thiostatin (TST) mRNAs to adult levels. Fetal liver responded to inflammation of the mother by a transcriptional induction of all of the investigated APP genes, except for the Fb gene whose level of expression remained unchanged. The pattern of individual APP genes expression in maternal and fetal livers was similar and characteristic for the acute phase reaction.