Recent evidence suggests that Toll-like receptor4 (TLR4) is not only involved in innate immunity but isalso an important mediator of adverse left ventricularremodeling and heart failure following acute myocardialinfarction (MI). TLR4 is activated by lipopolysaccharide(LPS) but also by products of matrix degradation such ashyaluronic acid and heparan sulfate. Although cardioprotectiveproperties of adenosine (Ado) have been extensivelystudied, its potential to interfere with TLR4 activation isunknown. We observed that TLR4 pathway is activated inwhite blood cells from MI patients. TLR4 mRNA expressioncorrelated with troponin T levels (R2=0.75; P=0.01)but not with levels of white blood cells and C-reactiveprotein. Ado downregulated TLR4 expression at the surfaceof human macrophages (-50%, P<0.05). Tumor necrosisfactor-a production induced by the TLR4 ligands LPS,hyaluronic acid, and heparan sulfate was potently inhibitedby Ado (-75% for LPS, P<0.005). This effect wasreproduced by the A2A Ado receptor agonist CGS21680and the non-selective agonist NECA and was inhibited bythe A2A antagonist SCH58261 and the A2A/A2B antagonistZM241,385. In contrast, Ado induced a 3-fold increaseof TLR4 mRNA expression (P=0.008), revealing theexistence of a feedback mechanism to compensate for theloss of TLR4 expression at the cell surface. In conclusion,the TLR4 pathway is activated after MI and correlates withinfarct severity but not with the extent of inflammation.Reduction of TLR4 expression by Ado may thereforerepresent an important strategy to limit remodeling post-MI.