The kidney as a second site of human C-reactive protein formation in vivo

Abstract Background Inflammatory bowel diseases (IBD) are characterized by an increased thrombosis risk of uncertain etiology. Coagulation derangement arising from inflammation may be a triggering factor. We hypothesized that strong inflammation inhibitors (eg, anti-tumor necrosis factor-α drugs) may affect coagulation. Methods Forty patients with IBD were compared with 57 control patients for coagulation factors and endogenous thrombin potential (ETP), the latter being the most sensitive marker of in vivo pro- and anticoagulation balance. We measured ETP in the presence and absence of thrombomodulin (the physiologic protein C [PC] activator). Coagulation at different timepoints was also assessed for 28 of these patients during infliximab treatment. Results The median ETP (nM thrombin × minutes) and range (minimum-maximum) were each higher in patients at baseline than in control patients in both the absence (2120 [1611-3041] vs 1865 [1270-2337]) and the presence (1453 [464-2522] vs 831 [104-1741]) of thrombomodulin. The ETP ratio (with/without thrombomodulin) was high at baseline (0.73 [0.21-0.90] vs 0.45 [0.07-0.85]). The ETP and ETP ratio declined during treatment and were significantly lower at the end than at baseline. Factor (F) VIII and fibrinogen, which were high at baseline, decreased during treatment and at the end were significantly lower than at baseline. The FVIII/PC ratio, which was high in patients at baseline, declined during treatment and at the end was lower than at baseline. C-reactive protein recorded at the end of treatment was lower than at baseline. Conclusions Patients with IBD have a procoagulant imbalance as shown by increased ETP at baseline. The ETP decreases during treatment with infliximab, which is related to decreased FVIII and FVIII/PC ratio. This effect is also related to the improvement of inflammation as shown by decreased fibrinogen and C-reactive protein.

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

Hypertension ◽

10.1161/hyp.62.suppl_1.a277 ◽

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.

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Influence of apolipoprotein E genotype and dietary α-tocopherol on redox status and C-reactive protein levels in apolipoprotein E3 and E4 targeted replacement mice

British Journal Of Nutrition ◽

10.1017/s000711450788634x ◽

2008 ◽

Vol 100 (1) ◽

pp. 44-53 ◽

Cited By ~ 10

Author(s):

Laia Jofre-Monseny ◽

Patricia Huebbe ◽

Inken Stange ◽

Christine Boesch-Saadatmandi ◽

Jan Frank ◽

...

Keyword(s):

Apoe Genotype ◽

Positive Association ◽

Thiobarbituric Acid ◽

Redox Status ◽

C Reactive Protein ◽

Cvd Risk ◽

Reactive Protein ◽

Antioxidant Defence System

The molecular basis of the positive association between apoE4 genotype and CVD remains unclear. There is direct in vitro evidence indicating that apoE4 is a poorer antioxidant relative to the apoE3 isoform, with some indirect in vivo evidence also available. Therefore it was hypothesised that apoE4 carriers may benefit from α-tocopherol (α-Toc) supplementation. Targeted replacement mice expressing the human apoE3 and apoE4 were fed with a diet poor (0 mg/kg diet) or rich (200 mg/kg diet) in α-Toc for 12 weeks. Neither apoE genotype nor dietary α-Toc exerted any effects on the antioxidant defence system, including glutathione, catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase activities. In addition, no differences were observed in mitogen-induced lymphocyte proliferation. α-Toc concentrations were modestly higher in plasma and lower in tissues of apoE4 compared with apoE3 mice, with the greatest differences evident in the lung, suggesting that an apoE4 genotype may reduce α-Toc delivery to tissues. A tendency towards increased plasma F2-isoprostanes in apoE4 mice was observed, while liver thiobarbituric acid-reactive substances did not differ between apoE3 and apoE4 mice. In addition, C-reactive protein (CRP) concentrations were reduced in apoE4 mice indicating that this positive effect on CRP may in part negate the increased CVD risk associated with an apoE4 genotype.

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4P-1178 Direct in vivo down-regulation of IL-1-induced C-reactive protein (CRP) expression by statins and fibrates in human CRP transgenic mice

Atherosclerosis Supplements ◽

10.1016/s1567-5688(03)91434-6 ◽

2003 ◽

Vol 4 (2) ◽

pp. 334

Author(s):

H. Princen ◽

B.-J. De Rooij ◽

A.J. Szalai ◽

M. De Maat ◽

T. Kooistra ◽

...

Keyword(s):

Transgenic Mice ◽

C Reactive Protein ◽

Down Regulation ◽

Reactive Protein

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C-Reactive Protein and Complement Are Important Mediators of Tissue Damage in Acute Myocardial Infarction

Journal of Experimental Medicine ◽

10.1084/jem.190.12.1733 ◽

1999 ◽

Vol 190 (12) ◽

pp. 1733-1740 ◽

Cited By ~ 349

Author(s):

M. Griselli ◽

J. Herbert ◽

W.L. Hutchinson ◽

K.M. Taylor ◽

M. Sohail ◽

...

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Acute Phase ◽

Acute Phase Response ◽

Myocardial Injury ◽

Peak Plasma ◽

C Reactive Protein ◽

Reactive Protein ◽

Coronary Ligation

Myocardial infarction in humans provokes an acute phase response, and C-reactive protein (CRP), the classical acute phase plasma protein, is deposited together with complement within the infarct. The peak plasma CRP value is strongly associated with postinfarct morbidity and mortality. Human CRP binds to damaged cells and activates complement, but rat CRP does not activate complement. Here we show that injection of human CRP into rats after ligation of the coronary artery reproducibly enhanced infarct size by ∼40%. In vivo complement depletion, produced by cobra venom factor, completely abrogated this effect. Complement depletion also markedly reduced infarct size, even when initiated up to 2 h after coronary ligation. These observations demonstrate that human CRP and complement activation are major mediators of ischemic myocardial injury and identify them as therapeutic targets in coronary heart disease.

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IMMUNOLOGIC CROSS-REACTIONS AMONG MAMMALIAN ACUTE PHASE PROTEINS

Journal of Experimental Medicine ◽

10.1084/jem.111.4.441 ◽

1960 ◽

Vol 111 (4) ◽

pp. 441-451 ◽

Cited By ~ 13

Author(s):

Emil Gotschlich ◽

Chandler A. Stetson

Keyword(s):

Acute Phase ◽

Guinea Pigs ◽

Acute Phase Proteins ◽

Double Diffusion ◽

Cross Reactivity ◽

C Reactive Protein ◽

Skin Reactions ◽

Cross Reactions ◽

Reactive Protein

Crystalline rabbit Cx-reactive protein has been compared immunologically with the analogous crystalline C-reactive protein of man. Immunologic cross-reactivity has been demonstrated between the acute phase proteins of man, rabbit, and monkey. Double-diffusion reactions in agar and passive cutaneous anaphylaxis reactions in vivo both indicate that these acute phase proteins are antigenically closely similar but not identical. Guinea pigs with delayed hypersensitivity to C-reactive protein exhibit delayed skin reactions when tested with Cx-reactive protein and vice versa.

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C-Reactive Protein Adversely Alters the Protein–Protein Interaction of the Endothelial Isoform of Nitric Oxide Synthase

Clinical Chemistry ◽

10.1373/clinchem.2009.142364 ◽

2010 ◽

Vol 56 (8) ◽

pp. 1345-1348 ◽

Cited By ~ 11

Author(s):

Simona Valleggi ◽

Sridevi Devaraj ◽

Mohan R Dasu ◽

Ishwarlal Jialal

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Protein Interactions ◽

Heat Shock Protein 90 ◽

C Reactive Protein ◽

Caveolin 1 ◽

Reactive Protein ◽

Oxide Synthase

BACKGROUND C-reactive protein (CRP) inhibits the activity of the endothelial isoform of nitric oxide synthase (eNOS) via uncoupling of the enzyme both in vitro and in vivo. eNOS activity appears to be related in part to its interaction with other cellular proteins, including heat shock protein 90 (Hsp90), caveolin-1, and porin. In this study, we examined the effect of CRP treatment of human aortic endothelial cells (HAECs) on eNOS interaction with caveolin-1, Hsp90, and porin. METHODS We incubated HAECs with CRP (0, 12.5, and 25 mg/L) for 1, 6, or 24 h and assessed the interaction of these proteins with eNOS by immunoprecipitation and western blotting. RESULTS CRP treatment (12.5 and 25 mg/L) of HAECs for 24 h significantly increased eNOS binding to caveolin-1 (40% and 54% increase, respectively; P < 0.05) and decreased binding to Hsp90 (33% and 66% decrease, respectively; P < 0.05). CRP (25 mg/L) also significantly decreased the binding of porin to eNOS (11% decrease, P < 0.05). Similar results were seen when HAECs were treated with CRP for 6 h. CONCLUSIONS These negative protein–protein interactions of eNOS were able to partly explain the CRP-induced decreases in the activity of this critical enzyme, which caused endothelial dysfunction.

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Histone H4 potentiates neutrophil inflammatory responses to influenza A virus: Down-modulation by H4 binding to C-reactive protein and Surfactant protein D

PLoS ONE ◽

10.1371/journal.pone.0247605 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0247605

Author(s):

I-Ni Hsieh ◽

Mitchell White ◽

Marloes Hoeksema ◽

Xavier Deluna ◽

Kevan Hartshorn

Keyword(s):

Influenza A Virus ◽

Respiratory Burst ◽

Influenza A ◽

Inflammatory Responses ◽

Surfactant Protein ◽

Surfactant Protein D ◽

Histone H4 ◽

C Reactive Protein ◽

Reactive Protein

Neutrophils participate in the early phase of the innate response to uncomplicated influenza A virus (IAV) infection but also are a major component in later stages of severe IAV or COVID 19 infection where neutrophil extracellular traps (NETs) and associated cell free histones are highly pro-inflammatory. It is likely that IAV interacts with histones during infection. We show that histone H4 binds to IAV and aggregates viral particles. In addition, histone H4 markedly potentiates IAV induced neutrophil respiratory burst responses. Prior studies have shown reactive oxidants to be detrimental during severe IAV infection. C reactive protein (CRP) and surfactant protein D (SP-D) rise during IAV infection. We now show that both of these innate immune proteins bind to histone H4 and significantly down regulate respiratory burst and other responses to histone H4. Isolated constructs composed only of the neck and carbohydrate recognition domain of SP-D also bind to histone H4 and partially limit neutrophil responses to it. These studies indicate that complexes formed of histones and IAV are a potent neutrophil activating stimulus. This finding could account for excess inflammation during IAV or other severe viral infections. The ability of CRP and SP-D to bind to histone H4 may be part of a protective response against excessive inflammation in vivo.

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Discovery, in-vitro and in-vivo efficacy of an anti-inflammatory small molecule inhibitor of C-reactive protein

10.21203/rs.3.rs-944388/v1 ◽

2021 ◽

Author(s):

Johannes Zeller ◽

Karen Cheung Tung Shing ◽

Tracy Nero ◽

Guy Krippner ◽

James McFadyen ◽

...

Keyword(s):

Cell Activation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Acute Ischemia ◽

C Reactive Protein ◽

Endothelial Cell Activation ◽

Reactive Protein ◽

Anti Inflammatory

Abstract C-reactive protein (CRP) is an acute phase protein. We recently identified a novel mechanism that leads to a conformational change from the native, pentameric structure (pCRP) to a pentameric intermediate (pCRP*) and ultimately to the monomeric form, mCRP, both being highly pro-inflammatory. This ‘CRP activation’ is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine (PC) lipid head groups. We designed a low molecular weight pCRP – PC inhibitor, C10M. Binding assays and X-ray crystallography revealed direct, competitive binding of C10M to pCRP, blocking interaction with PC and thereby inhibiting formation of pCRP*/mCRP and their pro-inflammatory effects. The anti-inflammatory potential of C10M was confirmed in-vitro by various measures of leukocyte and endothelial cell activation and in-vivo in rat models of acute ischemia/reperfusion injury and hindlimb transplantation. In conclusion, inhibition of pCRP*/mCRP generation via the PC-mimicking compound C10M represents a promising, potentially broadly applicable anti-inflammatory therapy.

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Interplay Between IL-1, IL-6 and IL-17 in IL-1 Receptor Antagonist (IL-1Ra) Treated Multiple Myeloma Patients

Blood ◽

10.1182/blood.v120.21.1874.1874 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1874-1874

Author(s):

Kathleen A. Donovan ◽

Laurie L. Moon-Tasson ◽

John A Lust

Keyword(s):

Plasma Cells ◽

Early Stage ◽

Small Sample Size ◽

Small Sample ◽

Cell Labeling ◽

M Protein ◽

C Reactive Protein ◽

Minor Response ◽

Reactive Protein

Abstract Abstract 1874 In early stage myeloma, IL-6 is a central myeloma growth factor and we have shown that abnormal production of IL-1 in the myeloma microenvironment stimulates the generation of IL-6 in a paracrine fashion. IL-1 has also been shown to be a crucial factor in the induction of IL-17 producing T-cells in vivo. IL-1Ra is a specific blocker of IL-1 activity. We have previously reported on a Phase II trial using IL-1Ra and dexamethasone, in patients with smoldering/indolent MM (SMM/IMM), showing that IL-1Ra targets the myeloma proliferative component which parallels a decrease in the C-reactive protein (CRP), a surrogate for IL-6 production. These patients are the individuals most likely to benefit from anti-cytokine therapy in an attempt to delay/prevent the development of active myeloma. Patients that had > 10% bone marrow plasma cells and/or an IgG or IgA M-spike > 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of Anakinra (IL-1Ra) SQ qd for 6 months. Patients with evidence of reduction in M-protein levels continued receiving IL-1Ra alone. Patients with stable disease at 6 months or those with a rising M-protein before 6 months received low dose dexamethasone (20 mg qweek) in addition; the dose was adjusted based on response/toxicity. Data were available on 47 patients based on intent to treat, and patients were classified as smoldering (72%) vs. indolent (28%). All 47 patients received IL-1Ra initially and 25/47 subsequently received IL-1Ra/Dex. Myeloma cell growth rate (PCLI), C-reactive protein (an in vivo marker of IL-6 levels) and IL-17 were measured in patients on trial. Seven patients had a decrease in the plasma cell labeling index (PCLI) on IL-1Ra alone which paralleled a decrease in the C-reactive protein in all cases. Three patients achieved a minor response to IL-1Ra alone and 9 patients achieved a PR/MR after addition of dexamethasone. When patients were grouped into whether they exhibited a reduction in the C-reactive protein from baseline after 6 months of therapy, the median PFS for patients without (21 patients) or with (26 patients) a greater than one-third reduction in baseline CRP was 1 year vs more than 8 years (p<.01). Analyses of biomarkers suggest that patients with elevated IL-17 levels may be less likely to respond to IL-1Ra treatment. Only 25% of the responders with a decrease in CRP had IL-17 levels > 10 pg/ml versus 60% of those without a CRP decrease. Although not statistically significant do to the small sample size, the median PFS in the IL-17 < 10 pg/ml group was 2047days vs 1367 days in the IL-17 > 10 pg/ml group. In conclusion, the above results suggest that agents such as IL-1Ra that specifically inhibit IL-1 induced paracrine IL-6 production are effective at targeting the proliferative myeloma component and warrant further investigation in combination with standard myeloma therapies. Elevated IL-17 levels may suggest that the inflammatory process is too far advanced in some individuals to respond to IL-1 blockade. Biomarkers such as CRP and IL-17 may be useful to predict those patients that are most likely to benefit from IL-1 treatment. Disclosures: Off Label Use: IL-1Ra in myeloma.

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