Atrial fibrillation (AF) is the most common type of heart arrhythmia. Currently, the pathogenesis of AF is not fully understood yet. A growing body of evidence highlighted the strong association between inflammation and the pathogenesis of AF. C-reactive protein (CRP) is an inflammation marker with increased expression in AF. Therefore, the aim of this study was to determine if CRP promotes inflammation, which may sequentially mediate the onset of AF and the concurrent atrial fibrosis, through TLR4/NF-kappa B/TGF-beta pathway. HL-1 cells were treated with either 25 or 50 mu g/ml recombinant human CRP. TGF-beta 1 and NF-kappa B inhibitors were given either solely or together to the 50 mu g/ml CRP-treated cells. Cell proliferation, apoptosis, the expression of apoptotic factors and TLR4, IL-6, TGF-beta 1, Smad2, and the phosphorylation of Smad2 were determined. Data showed that CRP induced dose-dependent inhibition on cell proliferation and promoted cell apoptosis, which was induced through both intrinsic and extrinsic pathways. Such effects were reversed by inhibiting TGF-beta 1 and/or NF-kappa B. Inhibition of TGF-beta 1 and/or NF-kappa B also reduced the expression of TLR4 and IL-6. Inhibition of NF-kappa B alone weakened the expression of TGF-beta 1 and phosphorylation of Smad2. Our study demonstrated that CRP is not only a marker, but also an important mediator in the induction of inflammation and likely the pathogenesis of AF. We for the first time reported CRP-induced activation and cross-talk between TLR4 and NF-kappa B/TGF-beta 1 signaling pathway in a cardiomyocyte model. Reducing CRP and targeting TLR4/NF-kappa B/TGE-beta 1 pathway may provide new insights in the therapeutic interventions to inflammation-induced AF.