scholarly journals Platelet-Activating Factor Induces Th17 Cell Differentiation

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Anne-Marie Drolet ◽  
Maryse Thivierge ◽  
Sylvie Turcotte ◽  
Dominique Hanna ◽  
Bruno Maynard ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Neutralizing Antibodies ◽  
Platelet Activating Factor ◽  
Activated T Cells ◽  
Inflammatory Lesions ◽  
Th17 Cell Differentiation ◽  
Enhanced Expression ◽  
Inflammatory Processes ◽  
Paf Receptor ◽  
Paf Receptor Antagonist

Th17 cells have been implicated in a number of inflammatory and autoimmune diseases. The phospholipid mediator platelet-activating factor (PAF) is found in increased concentrations in inflammatory lesions and has been shown to induce IL-6 production. We investigated whether PAF could affect the development of Th17 cells. Picomolar concentrations of PAF induced IL-23, IL-6, and IL-1βexpression in monocyte-derived Langerhans cells (LCs) and in keratinocytes. Moreover, when LC were pretreated with PAF and then cocultured with anti-CD3- and anti-CD28-activated T cells, the latter developed a Th17 phenotype, with a significant increase in the expression of the transcriptional regulator RORγt and enhanced expression of IL-17, IL-21, and IL-22. PAF-induced Th17 development was prevented by the PAF receptor antagonist WEB2086 and by neutralizing antibodies to IL-23 and IL-6R. This may constitute a previously unknown stimulus for the development and persistence of inflammatory processes that could be amenable to pharmacologic intervention.

Exogenous xanthine promotes neutrophil adherence to cultured endothelial cells

1997 ◽  
Vol 273 (2) ◽  
pp. G342-G347
Author(s):  
H. Ichikawa ◽  
R. E. Wolf ◽  
T. Y. Aw ◽  
N. Ohno ◽  
L. Coe ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Injury ◽  
Umbilical Vein ◽  
Platelet Activating Factor ◽  
Adhesion Assay ◽  
Neutrophil Adherence ◽  
Paf Receptor ◽  
Umbilical Vein Endothelial Cells ◽  
Adhesive Effect ◽  
Paf Receptor Antagonist

Oxidants generated by endothelial xanthine oxidase (XO) can help trigger free radical-mediated tissue injury. An important event in oxidant-mediated tissue injury is neutrophil-endothelial adhesion. Although activation of endothelial XO increases adhesion, little is known about xanthine in the adhesive effect of XO. This study examined administered xanthine on the adhesion of neutrophils. Endothelial [human umbilical vein endothelial cells (HUVEC)] monolayers were exposed to xanthine (15 min), and neutrophils were allowed to adhere to HUVEC in an adhesion assay. Adhesion was dose dependently increased by xanthine (3-100 microM). Either catalase (1,000 U/ml), oxypurinol (XO inhibitor; 100 microM), or platelet-activating factor (PAF) receptor antagonist (WEB 2086; 10 microM) reduced neutrophil adhesion. Superoxide dismutase (1,000 U/ml) had no effect. Pretreatment of HUVEC with 50 microM tungsten also blocked xanthine-induced adherence. Adhesion was also inhibited by preincubation with 100 U/ml heparin. Finally, anti-P-selectin antibody (PB1.3; 20 micrograms/ml) attenuated adhesion. Our results indicate that xanthine may promote neutrophil-endothelial adhesion via a hydrogen peroxide- and PAF-mediated P-selectin expression.

Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

2001 ◽  
Vol 100 (6) ◽  
pp. 601-607 ◽  
Author(s):  
Roger TAYLOR ◽  
Daniel FATOVICH ◽  
Thomas HITCHCOCK ◽  
Catherine MORRISON ◽  
Lloyd CURTIS
Keyword(s):  
Myocardial Infarction ◽  
Blood Pressure ◽  
Acute Myocardial Infarction ◽  
Receptor Antagonist ◽  
Platelet Activating Factor ◽  
Systolic Pressure ◽  
Induced Hypotension ◽  
Paf Receptor ◽  
Double Blinded ◽  
Paf Receptor Antagonist

Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n = 35), or matching placebo (n = 36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5×106 units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43±28 mmHg (mean±S.D.) and 40±26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to < 90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3±17.5 and 40.2±13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.

scholarly journals BCAP links IL-1R to the PI3K–mTOR pathway and regulates pathogenic Th17 cell differentiation

2018 ◽  
Vol 215 (9) ◽  
pp. 2413-2428 ◽  
Author(s):  
Krystin Deason ◽  
Ty Dale Troutman ◽  
Aakanksha Jain ◽  
Dilip K. Challa ◽  
Rajakumar Mandraju ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Activated T Cells ◽  
Th1 Cell ◽  
Th17 Cell Differentiation ◽  
Th 17 ◽  
Phosphoinositide 3 Kinase

The toll-like receptor (TLR) and interleukin (IL)–1 family of receptors share several signaling components, including the most upstream adapter, MyD88. We previously reported the discovery of B cell adapter for phosphoinositide 3-kinase (BCAP) as a novel toll–IL-1 receptor homology domain–containing adapter that regulates inflammatory responses downstream of TLR signaling. Here we find that BCAP plays a critical role downstream of both IL-1 and IL-18 receptors to regulate T helper (Th) 17 and Th1 cell differentiation, respectively. Absence of T cell intrinsic BCAP did not alter development of naturally arising Th1 and Th17 lineages but led to defects in differentiation to pathogenic Th17 lineage cells. Consequently, mice that lack BCAP in T cells had reduced susceptibility to experimental autoimmune encephalomyelitis. More importantly, we found that BCAP is critical for IL-1R–induced phosphoinositide 3-kinase–Akt–mechanistic target of rapamycin (mTOR) activation, and minimal inhibition of mTOR completely abrogated IL-1β–induced differentiation of pathogenic Th17 cells, mimicking BCAP deficiency. This study establishes BCAP as a critical link between IL-1R and the metabolic status of activated T cells that ultimately regulates the differentiation of inflammatory Th17 cells.

Platelet-activating factor primes neutrophil responses to agonists: role in promoting neutrophil-mediated endothelial damage

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1100-1107 ◽  
Author(s):  
GM Vercellotti ◽  
HQ Yin ◽  
KS Gustafson ◽  
RD Nelson ◽  
HS Jacob
Keyword(s):  
Endothelial Cells ◽  
Phorbol Esters ◽  
Platelet Activating Factor ◽  
Endothelial Damage ◽  
Polymorphonuclear Cells ◽  
Paf Antagonists ◽  
Enhanced Expression ◽  
Paf Receptor ◽  
Acid Metabolites ◽  
Subsequent Addition

Abstract During inflammation polymorphonuclear cells (PMNs) are exposed to agonistic stimuli including activated complement, kallikrein, arachidonic acid metabolites, monokines, and platelet-activating factor (PAF). We report that PAF not only directly activates PMNs but in miniscule quantities (10(-12) mol/L) “primes” them as well, that is, permits PMNs to respond to subsequent stimuli that would be otherwise ineffectual. PAF priming of responses including superoxide generation, elastase release, and aggregation is time dependent and is maximal within five minutes. PAF need not be present during the subsequent exhibition of PMN agonists, but priming is inhibited by cold and is also inhibited by the PAF receptor antagonists BN 52021, L-652, and kadsurenone. An intact PAF molecule is required because lyso-PAF and methoxy-PAF do not prime PMN responses. PAF priming is associated with both enhanced expression of the adhesive glycoprotein identified by OKM- 1 antibody and an enhanced rise in intracellular calcium levels in response to the subsequent addition of agonists such as FMLP. PMNs primed with PAF and stimulated with either F-Met-Leu-Phe or phorbol esters are more effective in lysing and detaching cultured human endothelial cells--damage that can also be inhibited by the PAF antagonists. Because PAF is synthesized and exhibited on surfaces of endothelial cells perturbed by coagulation, we suggest that this lipid may potentiate otherwise trivial activators of marginated PMNs so that they become damaging to the PAF-synthesizing endothelium itself. If so, our studies suggest a possible therapeutic role for PAF inhibitors in excessive inflammatory states.

scholarly journals Invasion of Human Vascular Endothelial Cells byActinobacillus actinomycetemcomitans via the Receptor for Platelet-Activating Factor

2000 ◽  
Vol 68 (9) ◽  
pp. 5416-5419 ◽  
Author(s):  
Harvey A. Schenkein ◽  
Suzanne E. Barbour ◽  
C. R. Berry ◽  
Barbara Kipps ◽  
John G. Tew
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Platelet Activating Factor ◽  
Systemic Circulation ◽  
Oral Bacteria ◽  
Periodontal Pathogen ◽  
Vascular Endothelial ◽  
Transmission Electron ◽  
Paf Receptor ◽  
Paf Receptor Antagonist

ABSTRACT Strains of the periodontal pathogen Actinobacillus actinomycetemcomitans are variable with respect to display of phosphorylcholine (PC)-bearing antigens. We have examined strains ofA. actinomycetemcomitans with and without PC to assess their ability to invade endothelial cells via the receptor for platelet-activating factor (PAF). Results of antibiotic protection assays indicate that PC-bearing A. actinomycetemcomitansinvade human vascular endothelial cells by a mechanism inhibitable by CV3988, a PAF receptor antagonist, and by PAF itself. The invasive phenotype was verified by transmission electron microscopy. A PC-deficient strain of this organism was not invasive. This property, in addition to the established ability of A. actinomycetemcomitans to invade epithelial cells, may provide this organism with access to the systemic circulation. The ability of PC-bearing oral bacteria to access the circulation may also explain the elevated levels of anti-PC antibody in serum found in patients with periodontitis.

scholarly journals Receptor mechanisms of PAF mediated lymphatic constriction in the canine forelimb

1992 ◽  
Vol 1 (6) ◽  
pp. 391-395 ◽  
Author(s):  
D. E. Dobbins
Keyword(s):  
Smooth Muscle ◽  
Receptor Antagonist ◽  
Lymphatic Vessel ◽  
Perfusion Pressure ◽  
Muscle Tone ◽  
Platelet Activating Factor ◽  
Arterial Infusion ◽  
Paf Receptor ◽  
Transport Fluid ◽  
Paf Receptor Antagonist

Platelet activating factor (PAF) is a potent inflammatory lipid. In this study we assessed the ability of PAF to impact lymphatic vessel function by altering prenodal lymphatic resistance. Intralymphatic PAF (7.47 × 10−6, 7.47 × 10−5and 7.47 × 10−4M) increased lymphatic perfusion pressure at the two highest infusion rates. PAF mediated lymphatic constriction was not altered by the intra-arterial infusion of phentolamine but was blocked by the intra-arterial infusion of the PAF receptor antagonist WEB 2170. These data indicate that in addition to PAF's effects on microvascular permeability, this agent may also impact the ability of the lymphatics to transport fluid through alterations in lymphatic smooth muscle tone. PAF mediated lymphatic constriction is not mediated by α-receptors but rather through PAF receptor mediated mechanism.

Effect of platelet-activating factor (PAF) receptor antagonist (BN52021) on acetaminophen-induced acute liver injury and regeneration in rats

2005 ◽  
Vol 26 (1) ◽  
pp. 97-105 ◽  
Author(s):  
A. D. Grypioti ◽  
S. E. Theocharis ◽  
C. A. Demopoulos ◽  
Z. Papadopoulou-Daifoti ◽  
A. C. Basayiannis ◽  
...  
Keyword(s):  
Liver Injury ◽  
Receptor Antagonist ◽  
Acute Liver Injury ◽  
Platelet Activating Factor ◽  
Paf Receptor ◽  
Paf Receptor Antagonist
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