Toll-like　receptor-mediated　NF-kappa　B　activation　is　a　major　innate　immune　reaction　of　vascular　endothelial　cells　(ECs)　in　response　to　prooxidative　and　proinflammatory　stimuli.　We　identified　that　TNF-alpha　receptor-associated　factor-interacting　protein　with　a　forkhead-associated　domain　(TIFA)　is　a　regulator　of　priming　(signal　1)　and　activating　(signal　2)　signals　of　nucleotide　oligomerization　domain-like　receptor　family　pyrin　domain-containing　protein　3　(NLRP3)　inflammasome　in　ECs.　Oxidative　and　inflammatory　stresses　such　as　atheroprone　flow　and　hyperlipidemia　induce　and　activate　TIFA　in　vitro　and　in　vivo.　For　the　priming　of　signal　1,　sterol　regulatory　element-binding　protein　2　transactivates　TIFA,　which　in　turn　induces　NF-kappa　B　activation　and　augments　the　transcription　of　NLRP3　inflammasome　components.　For　the　activation　of　signal　2,　Akt　is　involved　in　TIFA　Thr9　phosphorylation,　which　is　essential　for　TIFA-TIFA　homophilic　oligomerization.　Thr9　phosphorylation-dependent　TIFA　oligomerization　facilitates　the　higher-order　assembly　of　NLRP3　inflammasome,　as　indicated　by　the　interaction　between　TIFA　and　caspase-1　in　the　activated　ECs.　Our　results　suggest　that　TIFA　is　a　crucial　mediator　in　the　endothelial　innate　immune　response　by　potentiating　and　amplifying　NLRP3　inflammasome　via　augmenting　signals　1　and　2.