Inhibition of the activity of pro-inflammatory secretory phospholipase A2by acute phase proteins

Pro-Inflammatory non-pancreatic phospholipase A2(sPLA2) is markedly over-expressed in acute systemic and chronic local inflammatory processes. Since in acute phase reaction sPLA2is often over-expressed simultaneously with acute phase proteins (APP), it is important to determine whether APP interacts with sPLA2. We tested ten APPs for interaction with sPLA2using as a substrate multilamellar Hposomes composed either of PC:Lyso PC or PE:Lyso PE. Using PC:Lyso PC substrate, CRP, lactoferrin and SAP were found to inhibit sPLA2activity with an IC50of 25 μg/ml, 7.5 μg/ml and 50 μg/ml, respectively, corresponding to 0.21 μM, 0.1 μM and 0.21 μM respectively. Using PE:Lyso PE substrate only SAP was inhibitory, with an IC50of 10 μg/ml (0.04 μM). Phosphorylcholine abolished the inhibitory activity of CRP but not of SAP or lactoferrin. Addition of phosphorylethanolamine or of excess calcium had no effect on the inhibitory activity of APP. Limulin, lysozyme, transferrin, β2-microglobulin, α2-macroglobulin, human and bovine albumins had no effect on sPLA2 activity. Therefore neither the structure of pentraxins, or ironbinding, bacteriostatic property or amyloidogenic property preclude whether APP modulates sPLA2activity. Inhibition of pro-inflammatory sPLA2by APP may be one of the protective mechanisms of the acute phase reaction.

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Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man

Journal of Experimental Medicine ◽

10.1084/jem.20070120 ◽

2007 ◽

Vol 204 (8) ◽

pp. 1935-1944 ◽

Cited By ~ 42

Author(s):

Maren Luchtefeld ◽

Heribert Schunkert ◽

Monika Stoll ◽

Tina Selle ◽

Rachel Lorier ◽

...

Keyword(s):

Acute Phase ◽

Acute Phase Proteins ◽

Population Based ◽

Acute Phase Reaction ◽

Phase Reaction ◽

Signal Transducer ◽

Gp130 Receptor ◽

Independent Population ◽

Future Drug ◽

Artery Disease

Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population–based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.

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Acute phase reaction and acute phase proteins

Journal of Zhejiang University SCIENCE A ◽

10.1631/jzus.2005.b1045 ◽

2005 ◽

Vol 6B (11) ◽

pp. 1045-1056 ◽

Cited By ~ 499

Author(s):

E. Gruys ◽

M.J.M. Toussaint ◽

T.A. Niewold ◽

S.J. Koopmans

Keyword(s):

Acute Phase ◽

Acute Phase Proteins ◽

Acute Phase Reaction ◽

Phase Reaction

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The Effect of T-2 Toxin on the Acute Phase Reaction in Mice

Journal of the American College of Toxicology ◽

10.3109/10915818509014506 ◽

1985 ◽

Vol 4 (1) ◽

pp. 71-78 ◽

Cited By ~ 3

Author(s):

R. F. Dyck ◽

M.I.C. Issa ◽

S.L. Rogers ◽

F. Murphy ◽

G.G. Khachatourians

Keyword(s):

Acute Phase ◽

Acute Phase Response ◽

Acute Phase Proteins ◽

Tissue Injury ◽

Intraperitoneal Administration ◽

Phase Response ◽

Acute Phase Reaction ◽

Phase Reaction ◽

Trichothecene Mycotoxin ◽

Acute Phase Reactants

The effects of T-2 toxin on a murine model of the acute phase response were studied. Two murine acute phase reactants, serum amyloid P component and plasma fibronectin, were measured after subcutaneous and intraperitoneal administration of T-2 toxin in varying doses. No acute phase response was observed. Furthermore, T-2 toxin also blocked the acute phase reaction to subcutaneous AgNO3 in a dose-dependent fashion. These observations were not explained by damage to liver, the site of synthesis of acute phase proteins. Since the acute phase response is an immediate physiological reaction to tissue injury and may be a nonspecific participant in the repair phenomenon, its abrogation by T-2 toxin may contribute to the toxicity of this trichothecene mycotoxin.

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Lactoferrin gene expression upregulation in liver during turpentine oil- or bacterial LPS-induced acute phase reaction

Zeitschrift für Gastroenterologie ◽

10.1055/s-0031-1295798 ◽

2012 ◽

Vol 50 (01) ◽

Author(s):

G Ahmad ◽

GZK Sial ◽

P Ramadori ◽

J Dudas ◽

DS Batusic ◽

...

Keyword(s):

Gene Expression ◽

Acute Phase ◽

Acute Phase Reaction ◽

Phase Reaction ◽

Lactoferrin Gene

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Changes of gene expression of different BMP-proteins in liver in different mouse and rat models of acute phase reaction

Zeitschrift für Gastroenterologie ◽

10.1055/s-0034-1386433 ◽

2014 ◽

Vol 52 (08) ◽

Author(s):

S Ahmad ◽

F Moriconi

Keyword(s):

Gene Expression ◽

Acute Phase ◽

Acute Phase Reaction ◽

Phase Reaction ◽

Rat Models

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The inflammatory response and acute phase reaction in the liver upon LPS-treatment or partial hepatectomy is controlled by the MAPKAP kinases 2 and 3

Zeitschrift für Gastroenterologie ◽

10.1055/s-0037-1612823 ◽

2018 ◽

Vol 56 (01) ◽

pp. E2-E89

Author(s):

C Ehlting ◽

S Wolf ◽

M Hahnel ◽

O Böhmer ◽

U Albrecht ◽

...

Keyword(s):

Inflammatory Response ◽

Partial Hepatectomy ◽

Acute Phase ◽

Acute Phase Reaction ◽

Phase Reaction ◽

Lps Treatment

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Modulation of Plasma Fibrinogen Levels by Ticlopidine in Healthy Volunteers and Patients with Stable Angina Pectoris

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650547 ◽

1996 ◽

Vol 76 (02) ◽

pp. 166-170 ◽

Cited By ~ 11

Author(s):

Moniek P M de Maat ◽

Alf E R Arnold ◽

Stef van Buuren ◽

J H Paul Wilson ◽

Cornells Kluft

Keyword(s):

Angina Pectoris ◽

Healthy Volunteers ◽

Acute Phase ◽

Stable Angina ◽

Gene Polymorphisms ◽

Acute Phase Reaction ◽

Plasma Fibrinogen ◽

Phase Reaction ◽

Stable Angina Pectoris ◽

Lowering Effect

SummaryElevated plasma fibrinogen levels are associated with an increased risk for cardiac events. Ticlopidine is a drug that inhibits the ADP-induced aggregation of blood platelets and it also has been described that ticlopidine can decrease the plasma fibrinogen level in patients with vascular diseases. The mechanism of this decrease has not yet been elucidated and therefore mechanisms that are known to affect fibrinogen levels were studied, viz. the acute phase reaction, total fibrin plus fibrinogen degradation (TDP) levels and the polymorphisms of the fibrinogen β-gene.The fibrinogen lowering effect of ticlopidine was studied in 26 healthy volunteers, selected on genotype of the BclI polymorphism of the fibrinogen β-gene, and in 26 patients with stable angina pectoris in a double blind, randomized cross-over study. Functional plasma fibrinogen levels were measured with the Clauss assay. Fibrinogen antigen, C-reactive protein (CRP) and TDP levels were measured using an enzyme immuno assay (EIA).In the healthy volunteers the functional fibrinogen levels had decreased by 0.20 g/l (9%, p = 0.005 using the paired Student t-test) after 4 weeks of 250 mg bid ticlopidine administration, whereas fibrinogen antigen, CRP and TDP levels were not significantly changed. In the stable angina pectoris patients the pre-treatment fibrinogen, CRP and TDP levels were significantly higher than in the volunteer group. After four weeks 250 mg bid ticlopidine administration the functional fibrinogen levels had decreased by 0.38 g/l (11%, p < 0.005), whereas the fibrinogen antigen, CRP and TDP levels were not significantly changed. The levels of functional and antigen fibrinogen, CRP and TDP did not change significantly during the placebo period in the volunteers or the patients. Neither in the volunteers nor in the patients was the effect of ticlopidine on the fibrinogen levels associated with the fibrinogen β-gene polymorphisms.Therefore, the fibrinogen lowering effect of ticlopidine is likely to be a modulation of the functionality of the molecule and unlikely to be modulated by the acute phase reaction, TDP-levels or the fibrinogen β-gene polymorphisms.

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