Identification and characterization of a novel cytokine, THANK, a (T)under-barNF (H)under-baromologue that activates (A)under-barpoptosis, nuclear factor-kappa B, and c-Jun NH2-terminal (K)under-barinase

By using the amino acid sequence motif of tumor necrosis factor (TNF), we s earched the expressed sequence tag data base and identified a novel full-le ngth cDNA encoding 285 amino acid residues and named it THANK. THANK is a t ype II transmembrane protein with 15-20% overall amino acid sequence homolo gy to TNF, LT-alpha, Fast, and LIGHT, all members of the TNF family. The mR NA for THANK was expressed at high levels by peripheral blood leukocytes, l ymph node, spleen, and thymus and at low levels by small intestine, pancrea s, placenta, and lungs. THANK was also prominently expressed in hematopoiet ic cell lines. The recombinant purified protein expressed in the baculoviru s system had an approximate molecular size 20 kDa with amino-terminal seque nce of AVQGP. Treatment of human myeloid U937 cells with purified THANK act ivated nuclear transcription factor-kappa B (NF-kappa B) consisting of p50 and p65. Activation was time- and dose-dependent, beginning with as little as a 1 pM amount of the cytokines and as early as 15 min. Under the same co nditions, THANK also activated c-jun NH2-terminal kinase (JNK) in U937 cell s. THANK also strongly suppressed the growth of tumor cell lines and activa ted caspase-3. Although THANK had all the activities and potency of TNF, it did not bind to the TNF receptors. Thus our results indicate that THANK is a novel cytokine that belongs to the TNF family and activates apoptosis, N F-kappa B, and JNK through a distinct receptor.