Abstract 277: Elevated C-Reactive Protein Contributes to Preeclampsia via Kinin Signaling Pathways

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nicholas Parchim ◽  
Wei Wang ◽  
Takayuki Iriyama ◽  
Chen Liu ◽  
Athar H Siddiqui ◽  
...  
Keyword(s):  
Acute Phase Reactant ◽  
Receptor Activation ◽  
C Reactive Protein ◽  
Direct Role ◽  
Human Trophoblast ◽  
Reactive Protein ◽  
Induced Hypertension ◽  
Pregnant Mice

Preeclampsia (PE) is a serious pregnancy disease characterized by hypertension and proteinuria. Despite intensive research efforts, the underlying cause of PE remains a mystery. PE is, however, associated with abnormalities of the immune system. Here we report that the levels of C-reactive protein (CRP), an important acute phase reactant, were significantly elevated in the plasma of human with PE at the third trimester. Next, we found that CRP protein levels in the placentas of PE patients were also significantly increased compared to controls. In an effort to determine the exact role of elevated CRP in PE, we infused CRP into pregnant mice. We found that injection of CRP into pregnant mice induced hypertension (170 mmHg mean systolic vs. 125 mmHg mean systolic control; p<0.05) and proteinuria (25 mg/ug vs 12 mg/ug vehicle; p<0.05), indicating the direct role of CRP in PE. CRP is known to bind with phosphocholine on damaged cell membranes. Recent studies identified that neurokinin B (NKB), a placental enriched neuropeptide and known pathogenic molecule for PE, is phosphocholinated. This posttranslational modification increases its stability and enhances NKB-mediated receptor activation. These findings raise an intriguing hypothesis that CRP may bind with NKB coupled to NK3R activation and contribute to PE. To test this hypothesis, we conducted a pulldown assay, and we found that CRP bound with NKB. Next, using a cellular invasion assay, we revealed that CRP decreased invasion of human trophoblast cells (0.7 to 0.07 invasion index, p<0.05), while treatment with an NK3R selective antagonist, SB222200, ameliorated this shallow invasion. Finally, we provided in vivo evidence that inhibition of NK3R by SB222200 or knockdown of NK3R by specific siRNA in a potent nanoparticle delivery system significantly reduced CRP-induced hypertension and proteinuria in pregnant mice (170 mmHg mean systolic CRP-injected vs. 130 mmHg mean systolic siRNA NK3R; p<0.05 and proteinuria 25 mg/ug vs. 15 mg/ug; p<0.05). Overall, our findings demonstrate that elevated CRP contributes to PE and NKB/NK3R is a novel mechanism underlying CRP-mediated shallow invasion and disease development. These studies suggest novel pathogenic biomarkers and innovative therapeutic targets for PE.

scholarly journals The effect of interleukin-1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level

1995 ◽  
Vol 310 (1) ◽  
pp. 143-148 ◽  
Author(s):  
D Zhang ◽  
S L Jiang ◽  
D Rzewnicki ◽  
D Samols ◽  
I Kushner
Keyword(s):  
Interleukin 6 ◽  
Interleukin 1 ◽  
Kinetic Studies ◽  
Acute Phase Reactant ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Hep3b Cells

The combination of interleukin 6 (IL-6) and interleukin 1 (IL-1) synergistically induces the human acute-phase reactant, C-reactive protein (CRP) in Hep3B cells. While previous studies have indicated that IL-6 induces transcription of CRP, the mode of action of IL-1 has not been clearly defined. It has been suggested that the effect of IL-1 might be post-transcriptional, exerted through the 5′-untranslated region (5′-UTR). To evaluate the role of IL-1 in CRP gene expression, we studied the effects of interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) on both the endogenous CRP gene and on transfected CRP-CAT constructs in Hep3B cells. In kinetic studies of the endogenous CRP gene, IL-1 beta alone had no effect on CRP mRNA levels, but when added to IL-6, synergistically enhanced both CRP mRNA levels and transcription, as determined by Northern-blot analyses and nuclear run-on studies. IL-6 alone and the combination of [IL-1 beta + IL-6] each induced increases in mRNA levels roughly comparable with observed increases in transcription. These findings indicate that the effect of IL-1 beta on CRP expression is exerted largely at the transcriptional level in this system. This conclusion was confirmed by studies in Hep3B cells transiently transfected with CRP-CAT constructs, each containing 157 bp of the CRP 5′-flanking region but differing in the length of the 5′-UTR from 104 bp to 3 bp. All constructs responded in the same way; IL-6, but not IL-1 beta, induced significant chloramphenicol acetyltransferase (CAT) expression which was synergistically enhanced 2- to 3-fold by IL-1 beta. These results indicate that IL-1 beta stimulates transcriptional events in the presence of IL-6 and that the upstream 157 bases of the CRP promoter contain elements capable of both IL-6 induction and the synergistic effect of IL-1 beta on transcription.

scholarly journals C-Reactive Protein and Breast Cancer: New Insights from Old Molecule

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Shilpa Balaji Asegaonkar ◽  
Balaji Narayanrao Asegaonkar ◽  
Unmesh Vidyadhar Takalkar ◽  
Suresh Advani ◽  
Anand Pandurang Thorat
Keyword(s):  
Breast Cancer ◽  
Chronic Inflammation ◽  
Breast Cancer Survivors ◽  
Acute Phase Reactant ◽  
Therapeutic Interventions ◽  
Breast Cancer Patients ◽  
C Reactive Protein ◽  
Metabolic Disturbances ◽  
Reactive Protein

Recently an association between breast cancer and inflammation has emerged as the seventh hallmark of cancer. Chronic inflammation is a key contributor in the development and progression of carcinogenesis. Inflammatory pathways play an important role in the causation of breast cancer. C-reactive protein (CRP) an acute-phase reactant inflammatory protein is synthesized in hepatocytes in response to cytokines that are released from leucocytes within the tumor microenvironment. Several epidemiological studies appraised an association of CRP with breast cancer risk with inconsistent findings. Elevated levels at the time of diagnosis of breast cancer indicate aggressiveness of the tumor. CRP is also a well-established independent prognostic marker. Breast cancer survivors with the state of chronic inflammation are at risk of recurrence and metabolic disturbances. CRP lowering agents along with chemotherapeutic drugs will improve the survival of breast cancer patients. Also, it is a risk predictor for subsequent cardiotoxicity in patients receiving chemotherapy. The present review is aimed at elucidating the role of C-reactive protein, as an inflammatory risk marker and prognostic predictor of breast cancer. It also focuses on conflicting views on the role of CRP in breast cancer and its impact on therapeutic interventions.

scholarly journals Binding of C-reactive protein to modified low-density-lipoprotein particles: identification of cholesterol as a novel ligand for C-reactive protein

2002 ◽  
Vol 367 (2) ◽  
pp. 403-412 ◽  
Author(s):  
Sanna TASKINEN ◽  
Petri T. KOVANEN ◽  
Hanna JARVA ◽  
Seppo MERI ◽  
Markku O. PENTIKÄINEN
Keyword(s):  
Cholesterol Oxidase ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Acute Phase Reactant ◽  
Cholesterol Esterase ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Modified Lipoproteins ◽  
Arterial Intima

C-reactive protein (CRP), an acute-phase reactant, is present in atherosclerotic human arterial intima in association with lipids. In the present work we studied interactions between CRP and LDL on microtitre wells, where either CRP or LDL was immobilized. LDL was modified by vortex-mixing, oxidation, or by lipolysis with phospholipase A2 or with sphingomyelinase or a combination of trypsin and cholesterol esterase. We found that CRP bound only to LDL modified by trypsin/cholesterol esterase or by sphingomyelinase and that this binding was Ca2+-dependent. In these two forms of modified LDL, non-esterified cholesterol was susceptible to cholesterol oxidase, indicating exposure of non-esterified cholesterol on particle surfaces and suggesting a role for non-esterified cholesterol in mediating CRP binding. Consistent with this hypothesis were the following findings: (i) increasing the amount of non-esterified cholesterol in LDL with cyclodextrin increased, and decreasing its amount decreased, the binding of CRP to LDL; (ii) modification of non-esterified cholesterol in LDL by cholesterol oxidase decreased the binding of CRP to LDL; and (iii) CRP bound to purified non-esterified cholesterol. The binding was Ca2+-dependent and could be competed out with phosphocholine. Taken together, these findings suggest that CRP can bind to modified lipoproteins, notably to the non-esterified cholesterol on their surface. These interactions may be related to the suggested role of CRP in the local inflammation present in atherosclerotic plaques.

scholarly journals A Review of Anti-C Reactive Protein Antibodies in Systemic Lupus Erythematosus

2021 ◽  
Vol 6 (2) ◽  
pp. 60-66
Author(s):  
Patricia Richter ◽  
Alexandra Burlui ◽  
Ioana Bratoiu ◽  
Anca Cardoneanu ◽  
Ciprian Rezus ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Acute Phase Reactant ◽  
C Reactive Protein ◽  
Systemic Lupus ◽  
Reactive Protein ◽  
Phase Reactant ◽  
Alkaline Conditions ◽  
The Relationship

Abstract Systemic lupus erythematosus (SLE), the prototype autoimmune disease, is characterized by the production of a plethora of autoantibodies with various roles in the development of disease-related tissue damage. C-reactive protein (CRP) is an acute phase reactant with a pentameric structure. Under acidic or alkaline conditions, or when urea levels are high and/or calcium levels are low, the pentamer (pCRP) dissociates irreversibly into monomeric CRP (mCRP) and exposes new epitopes (neo-CRP). Importantly, anti-mCRP (but not anti-pCRP) antibodies have been described in patients with SLE, their prevalence varying from 4% to 78% in different cohorts. Numerous studies have investigated the relationship between autoantibodies directed against CRP (anti-CRP) and disease activity as well as their association with lupus nephritis (LN), frequently reporting discrepant findings. The main objective of the present review is to describe the role of anti-mCRP antibodies in SLE according to the currently available data.

scholarly journals Interleukin-6 is necessary, but not sufficient, for induction of the humanC-reactive protein gene in vivo

1997 ◽  
Vol 325 (3) ◽  
pp. 617-621 ◽  
Author(s):  
Birgit WEINHOLD ◽  
Augustinus BADER ◽  
Valeria POLI ◽  
Ulrich RÜTHER
Keyword(s):  
Transgenic Mice ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Acute Phase Reactant ◽  
Primary Hepatocytes ◽  
Cytokine Network ◽  
Gene Encoding ◽  
Reactive Protein

We have investigated the involvement of interleukin-6 (IL-6) in the induction of the gene encoding the acute-phase protein human C-reactive protein (hCRP). In transgenic mice the hCRP gene can be induced by lipopolysaccharide (LPS), but not by IL-6. In contrast, hCRP was inducible by IL-6 in primary human hepatocytes and in primary hepatocytes isolated from transgenic mice. To further evaluate the role of IL-6, we introduced the hCRP transgene into animals lacking endogenous IL-6 (IL-6-negative mice). Here, hCRP was not inducible by LPS, but was induced by a combination of LPS and IL-6. These results clearly demonstrate that IL-6 is necessary, but not sufficient, for the induction of hCRP expression. These animal models will allow further dissection of the cytokine network responsible for the regulation of the major human acute-phase reactant CRP.

Inhibition of C5a des Arg-induced neutrophil alveolitis in transgenic mice expressing C-reactive protein

1994 ◽  
Vol 266 (6) ◽  
pp. L649-L654 ◽  
Author(s):  
R. M. Heuertz ◽  
D. Xia ◽  
D. Samols ◽  
R. O. Webster
Keyword(s):  
Transgenic Mice ◽  
Elevated Serum ◽  
Neutrophil Infiltration ◽  
Serum Levels ◽  
Lavage Fluid ◽  
Acute Phase Reactant ◽  
C Reactive Protein ◽  
Reactive Protein

C-reactive protein (CRP) is the classic acute phase reactant in man with serum levels elevated up to 1,000-fold after the onset of inflammation. CRP inhibits chemotaxis of complement (C5a)-stimulated neutrophils in vitro and rabbits with elevated serum CRP levels exhibit diminished neutrophil infiltration and vascular permeability in a model of C5a-induced alveolitis. To specifically evaluate the effect of CRP on C5a-induced neutrophil inflammation in vivo, experiments were performed in transgenic mice capable of expressing rabbit CRP in an inducible fashion. After direct instillation of a known inflammatory agent (C5a des Arg) into the airways, transgenic mice with high plasma levels of CRP showed significantly diminished infiltration of neutrophils into bronchoalveolar lavage fluid (BALF) and a significant reduction of BALF total protein levels compared with normal mice. These data indicate that CRP can diminish lung injury by a reduction in neutrophil influx and protein leakage into alveoli following complement-induced inflammation.

scholarly journals In Vivo Confirmation of the Role of Statins in Reducing Nitric Oxide and C-Reactive Protein Levels in Peripheral Arterial Disease

2009 ◽  
Vol 37 (4) ◽  
pp. 443-447 ◽  
Author(s):  
E. Martínez Aguilar ◽  
J. De Haro Miralles ◽  
A. Flórez González ◽  
C. Varela Casariego ◽  
S. Bleda Moreno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Peripheral Arterial Disease ◽  
Arterial Disease ◽  
C Reactive Protein ◽  
Protein Levels ◽  
Reactive Protein ◽  
Peripheral Arterial

scholarly journals Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

Circulation ◽  
2014 ◽  
Vol 130 (1) ◽  
pp. 35-50 ◽  
Author(s):  
Jan R. Thiele ◽  
Jonathon Habersberger ◽  
David Braig ◽  
Yvonne Schmidt ◽  
Kurt Goerendt ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Phospholipase A2 ◽  
Striated Muscle ◽  
Inflammatory Cells ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Protein Dissociation

Background— The relevance of the dissociation of circulating pentameric C-reactive protein (pCRP) to its monomeric subunits (mCRP) is poorly understood. We investigated the role of conformational C-reactive protein changes in vivo. Methods and Results— We identified mCRP in inflamed human striated muscle, human atherosclerotic plaque, and infarcted myocardium (rat and human) and its colocalization with inflammatory cells, which suggests a general causal role of mCRP in inflammation. This was confirmed in rat intravital microscopy of lipopolysaccharide-induced cremasteric muscle inflammation. Intravenous pCRP administration significantly enhanced leukocyte rolling, adhesion, and transmigration via localized dissociation to mCRP in inflamed but not noninflamed cremaster muscle. This was confirmed in a rat model of myocardial infarction. Mechanistically, this process was dependent on exposure of lysophosphatidylcholine on activated cell membranes, which is generated after phospholipase A2 activation. These membrane changes could be visualized intravitally on endothelial cells, as could the colocalized mCRP generation. Blocking of phospholipase A2 abrogated C-reactive protein dissociation and thereby blunted the proinflammatory effects of C-reactive protein. Identifying the dissociation process as a therapeutic target, we stabilized pCRP using 1,6-bis(phosphocholine)-hexane, which prevented dissociation in vitro and in vivo and consequently inhibited the generation and proinflammatory activity of mCRP; notably, it also inhibited mCRP deposition and inflammation in rat myocardial infarction. Conclusions— These results provide in vivo evidence for a novel mechanism that localizes and aggravates inflammation via phospholipase A2–dependent dissociation of circulating pCRP to mCRP. mCRP is proposed as a pathogenic factor in atherosclerosis and myocardial infarction. Most importantly, the inhibition of pCRP dissociation represents a promising, novel anti-inflammatory therapeutic strategy.

Abstract 2673: C-reactive Protein Increases The Severity Of Stroke Outcome In Mice

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Dmitriy N Atochin ◽  
Helen Swanson ◽  
Chieko Mineo ◽  
Philip W Shaul ◽  
Paul L Huang
Keyword(s):  
Vascular Reactivity ◽  
Phosphorylation Site ◽  
Acute Phase Reactant ◽  
Stroke Outcome ◽  
C Reactive Protein ◽  
Doppler Flowmetry ◽  
Reactive Protein ◽  
Inflammatory Conditions ◽  
Cerebral Reperfusion

C-reactive protein (CRP) is an acute-phase reactant that is elevated in a variety of chronic inflammatory conditions including obesity and autoimmune disorders. Elevated CRP is associated with greater incidence and severity of stroke. However, it is unknown whether CRP directly impacts the severity of stroke outcome. We previously demonstrated that CRP antagonizes endothelial NO synthase (eNOS) by attenuating eNOS serine 1176 phosphorylation via the activation of SHIP-1 in endothelium, which blunts signaling downstream of PI3 kinase. Furthermore, we have shown that modulation of the eNOS serine 1176 phosphorylation site affects vascular reactivity and determines stroke size in vivo. We therefore hypothesize that CRP increases stroke vulnerability in vivo by altering the phosphorylation state of eNOS. To test our hypothesis, we subjected wild-type (WT) and CRP transgenic mice (TG-CRP), which have modest elevations in CRP, to a stroke model of temporal focal ischemia with subsequent reperfusion. Mean blood pressure measured acutely from the common carotid artery under aerrane anesthesia (30 % oxygen, 70% nitrous oxide and 1.5% aerrane) was similar in TG-CRP mice (96 ± 8 mmHg, Mean ± SD, n=6) and WT mice (93 ± 9 mmHg, n=14). Using Laser Doppler flowmetry, we monitored cerebral blood flow (CBF) above the middle cerebral artery (MCA) during 30 minutes of MCA occlusion (MCAO) provoked by a filament and during the first 30 minutes of subsequent reperfusion. Although there was a directional trend, in TG-CRP mice CBF reperfusion after 30 minutes (55 ± 34 %, n=5) was not different from WT mice (80 ± 16 %, n=5, P=0.28). However, the TG-CRP mice demonstrated markedly larger infarct volumes as compared with WT mice after 30 minutes of MCAO and 48 hours of reperfusion (100 ± 26 mm3 in TG-CRP vs. 51 ± 21 mm3 in WT, n=5/group, p< 0.03). Neurological deficit after 48 hours of reperfusion was also worse in TG-CRP mice (3.0 points) as compared with WT mice (1.8 point). These findings indicate that CRP increases the severity of stroke outcome in a mouse model of cerebral reperfusion. As such, future therapies aimed at CRP or its mechanism of action in stroke may potentially prevent or improve the stroke outcomes in patients with chronic inflammatory conditions such as obesity.

Sign in / Sign up

Export Citation Format

Share Document