Evidence for anti-inflammatory activity of statins and PPARα activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4188-4194 ◽  
Author(s):  
Robert Kleemann ◽  
Lars Verschuren ◽  
Bert-Jan de Rooij ◽  
Jan Lindeman ◽  
Moniek M. de Maat ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Nuclear Translocation ◽  
Plasma Cholesterol ◽  
Luciferase Reporter ◽  
Transcriptional Level ◽  
C Reactive Protein ◽  
Cholesterol Lowering ◽  
Reactive Protein ◽  
Anti Inflammatory

Abstract Inflammatory processes, aside from cholesterol, play a central role in atherogenesis. Human C-reactive protein (huCRP) signals systemic inflammation and independently predicts future cardiovascular risk. Cholesterol-lowering statins reduce atherosclerosis and plasma huCRP levels. Evidence is sought for a direct anti-inflammatory statin effect in vivo, independent of effects on plasma cholesterol and atherogenesis. The effect of atorvastatin and simvastatin on huCRP expression was studied in nonatherosclerotic huCRP transgenic mice and compared with another class of hypolipidemic drugs, peroxisome proliferator-activated receptor-alpha (PPARα) activators, notably fenofibrate and Wy14643. Like statins, PPARα activators combine antiatherosclerotic properties with huCRP-lowering effects. Dietary treatment with statins or PPARα activators decreased basal and interleukin-1β (IL-1β)-induced plasma huCRP levels independently of cholesterol lowering. These direct anti-inflammatory in vivo effects occurred at the transcriptional level and could be confirmed in cultured human liver slices and in human hepatoma cells transiently transfected with a huCRP promoter-driven luciferase reporter. A molecular rationale for the suppression of IL-1-induced huCRP transcription is provided by showing that statins and PPARα activators up-regulate IκBα protein expression. This results in a reduced nuclear translocation of p50-nuclear factor κ B (NFκB) and thereby decreased amounts of nuclear p50-NFκB∼CCAAT/enhancer binding protein beta (C/EBPβ) complexes, which determine the huCRP transcription rate. Our results provide conclusive evidence for a direct suppressive effect of statins and PPARα activators on huCRP expression independent of cholesterol lowering and atherogenesis. (Blood. 2004;103:4188-4194)

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

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

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

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.

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.

C-reactive protein induces pro- and anti-inflammatory effects, including activation of the liver X receptor α, on human monocytes

2008 ◽  
Vol 99 (03) ◽  
pp. 558-569 ◽  
Author(s):  
Armelle Ropars ◽  
Carole Seguin-Devaux ◽  
Gaël Poitevin ◽  
Sandrine Grosjean ◽  
Vèronique Latger-Cannard ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Nuclear Translocation ◽  
Liver X Receptor ◽  
Receptor Expression ◽  
Human Monocytes ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Markers Of Inflammation ◽  
Custom Made ◽  
Anti Inflammatory

SummaryNon-specific markers of inflammation such as C-reactive protein (CRP) are associated statistically with an increased risk of atherosclerosis through mechanisms that have not yet been fully elucidated.We investigated the effects of CRP on several aspects of human monocyte biology, a cell type involved in the initiation and progression of atherosclerosis. Blood monocytes isolated from healthy men and premenopausal women (n=9/group) were exposed to purified CRP (25 μg/ml) for 12 hours. Changes in gene expression were analyzed using a custom-made array containing oligonucleotide sequences of 250 genes expressed by activated monocytes and confirmed by quantitative PCR. CRP increased significantly the expression of the cytokines interleukin (IL)-1α, IL-1β and IL-6, and the chemokines GRO-α, GRO-β and IL-8. CRP also displayed anti-inflammatory effects through upregulation of liver X receptor (LXR) α and activin receptor expression, and down-regulation of alpha 2-macroglobulin expression. Increased LXRα mRNA expression in both monocytes and the monocytic cell lineTHP-1 was associated with increased LXRα protein expression and nuclear translocation, as well as increased ABCA1 mRNA expression, a target gene of LXRα. Western Blot analysis revealed CRP-induced nuclear translocation of NF-κB and activation of p42/44, MAP and Akt kinases. CRP-induced LXRá mRNA expression was inhibited by anti-CD64 (FcγRI) antibodies and by p42/44 and PI3 kinase inhibitors. This hypothesis-generating study demonstrates that CRP modulates the expression of genes that contribute to both pro- and anti-inflammatory responses in human monocytes. Among these novel anti-inflammatory effects, we show clearly that CRP activates the LXRα pathway.

scholarly journals C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms

2021 ◽  
Vol 12 ◽  
Author(s):  
Lawrence A. Potempa ◽  
Ibraheem M. Rajab ◽  
Margaret E. Olson ◽  
Peter C. Hart
Keyword(s):  
Protein Structures ◽  
Biological Response ◽  
Biological Response Modifier ◽  
C Reactive Protein ◽  
Functional Activities ◽  
Reactive Protein ◽  
Anti Inflammatory ◽  
Cancer Agent

C-reactive protein (CRP) was first recognized in the 1940s as a protein that appeared in blood during acute episodes of infectious disease. Its presence and pharmacodynamics were found in essentially all diseases that involved tissue damage and inflammation. Identified as a major component of the innate, unlearned immunity, it became a useful diagnostic marker for the extent of inflammation during disease exacerbation or remission. Efforts to define its true biological role has eluded clear definition for over a half-century. Herein, a unifying concept is presented that explains both pro-inflammatory and anti-inflammatory activities of CRP. This concept involves the recognition and understanding that CRP can be induced to undergo a pronounced, non-proteolytic reorganization of its higher-level protein structures into conformationally distinct isomers with distinctive functional activities. This process occurs when the non-covalently associated globular subunits of the pentameric isoform (“pCRP”) are induced to dissociate into a monomeric isoform (“mCRP”). mCRP consistently and potently provides pro-inflammatory activation and amplification activities. pCRP provides weak anti-inflammatory activities consistent with low-level chronic inflammation. mCRP can spontaneously form in purified pCRP reagents in ways that are not immediately recognized during purification and certification analyses. By now understanding the factors that influence pCRP dissociate into mCRP, many published reports investigating CRP as a biological response modifier of host defense can be reevaluated to include a discussion of how each CRP isoform may have affected the generated results. Specific attention is given to in vitro and in vivo studies of CRP as an anti-cancer agent.

Anti-TNF-α Treatment Reduces the Baseline Procoagulant Imbalance of Patients With Inflammatory Bowel Diseases

2021 ◽  
Author(s):  
Armando Tripodi ◽  
Luisa Spina ◽  
Laura Francesca Pisani ◽  
Lidia Padovan ◽  
Flaminia Cavallaro ◽  
...  
Keyword(s):  
Inflammatory Bowel Diseases ◽  
Coagulation Factors ◽  
Infliximab Treatment ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Thrombosis Risk ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Factor Α

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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