title: Tumour necrosis factor alpha upregulates platelet CD40L in patients with heart failure.
abstract: OBJECTIVE
  Patients with heart failure (HF) have elevated values of the pro-inflammatory protein CD40L but the underlying mechanism is unclear. This study was performed to evaluate the interplay between tumour necrosis factor alpha (TNFalpha) and CD40L in HF.
  
  
  RESULTS
  In patients with HF (n=86) and healthy subjects (HS, n=43), plasma levels of soluble CD40L (sCD40L), TNFalpha, soluble receptors of TNFalpha such as soluble TNF receptors I and II (sTNFR1 and sTNFR2), and 8OH-dG, a marker of oxidative stress, were determined. Also, an in vitro study was performed by determining platelet CD40L regulation upon platelet stimulation with TNFalpha. Compared with HS, HF patients had higher plasma values of sCD40L, TNFalpha, sTNFR1 and sTNFR2, and higher platelet expression of TNFR1 and TNFR2 with a progressive increase from NYHA I to NYHA IV classification. sCD40L significantly correlated with TNFalpha, sTNFR1, and sTNFR2; plasma levels of TNFalpha significantly correlated with sCD40L. Incubation of platelets from HF patients with a TNFalpha receptor inhibitor significantly decreased platelet CD40L expression. The in vitro study demonstrated that TNFalpha significantly increased CD40L expression, an effect weakly influenced by aspirin but significantly reduced by AACOCF3, an inhibitor of PLA(2), apocynin, an inhibitor of NADPH oxidase, or staurosporine, an inhibitor of PKC.
  
  
  CONCLUSIONS
  The study shows that in HF patients, platelet CD40L is upregulated by TNFalpha via a cyclooxygenase-1-independent, arachidonic acid-mediated oxidative stress mechanism.
authors.affiliation: IV Divisione di Clinica Medica, Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Policlinico Umberto I, 00185 Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pignatelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Cangemi
authors.forename: Andrea
authors.initials: A
authors.lastname: Celestini
authors.forename: Roberto
authors.initials: R
authors.lastname: Carnevale
authors.forename: Licia
authors.initials: L
authors.lastname: Polimeni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Martini
authors.forename: Domenico
authors.initials: D
authors.lastname: Ferro
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Loffredo
authors.forename: Francesco
authors.initials: F
authors.lastname: Violi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000098:Acetophenones / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D001095:Arachidonic Acids / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D023201:CD40 Ligand / Q000097:blood*; D016022:Case-Control Studies; D051545:Cyclooxygenase 1 / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D015854:Up-Regulation
chemical_list: D000098:Acetophenones; D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D064801:Phospholipase A2 Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C081565:arachidonyltrifluoromethane; D023201:CD40 Ligand; D000080242:8-Hydroxy-2'-Deoxyguanosine; C056165:acetovanillone; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D019255:NADPH Oxidases; D011493:Protein Kinase C; D054467:Phospholipases A2; D003849:Deoxyguanosine; D019311:Staurosporine; D001241:Aspirin