Analysis of tumor necrosis factor-α production and polymorphisms of the tumor necrosis factor-α gene in individuals with a history of Kawasaki disease

Background: Tumor necrosis factor (TNF)-alpha plays a central role in the pathogenesis of vasculitis in Kawasaki disease (KD). To address the genetic background of KD, we investigated the level of TNF-alpha production and genetic polymorphisms in the 5' flanking region of the TNF-alpha gene in healthy children with a history of KD. Methods: For TNF-alpha production, peripheral blood mononuclear cells (PBMC) of children with a history of ICD (n = 61) and of non-KD children (n = 35) were stimulated with phorbol 12-myristate 13-acetate, toxic shock syndrome toxin-1 (TSST-1) and the culture supernatant of Staphylococcus aureus derived from a KD patient (S-6), which had several superantigenic activities. The genetic background of KD was addressed by studying polymorphisms in the 5' flanking region of the TNF-alpha gene at positions - 1031 (thymine (T) to cytosine (C) change, termed - 1031C), - 863 (C to adenine (A), - 863A). - 857 (C to T, - 857T), - 308 (guanine (G) to A, - 308A) and - 238 (G to A, - 238A) in KD, using dot-blot hybridization with sequence-specific oligonucleotide probes. Results: The PBMC of KD patients with coronary artery lesions produced slightly higher levels of TNF-alpha in response to the bacterial products (such as TSST-1 and S-6). None of the polymorphisms in the 5' flanking region of the TNF-alpha gene were related to KD. Conclusions: These results suggest that a genetic disposition towards overproduction of TNF-alpha in response to bacterial products may be involved in the pathogenesis of KD.