Summary Involvement of excessive

SummaryWe have found previously that Txk, a member of the Tec family tyrosine kinases, is involved importantly in T helper 1 (Th1) cytokine production. However, how Txk regulates interferon (IFN)-g gene transcription in human T lymphocytes was not fully elucidated. In this study, we identified poly(ADPribose) polymerase 1 (PARP1) and elongation factor 1a (EF-1a) as Txkassociated molecules that bound to the Txk responsive element of the IFN-g gene promoter. Txk phosphorylated EF-1a and PARP1 formed a complex with them, and bound to the IFN-g gene promoter in vitro. In particular, the N terminal region containing the DNA binding domain of PARP1 was important for the trimolecular complex formation involving Txk, EF-1a and PARP1. Several mutant Txk which lacked kinase activity were unable to form the trimolecular complex. A PARP1 inhibitor, PJ34, suppressed IFN-g but not interleukin (IL)-4 production by normal peripheral blood lymphocytes (PBL). Multi-colour confocal analysis revealed that Txk and EF-1a located in the cytoplasm in the resting condition. Upon activation, a complex involving Txk, EF-1a and PARP1 was formed and was located in the nucleus. Collectively, Txk in combination with EF-1a and PARP1 bound to the IFN-g gene promoter, and exerted transcriptional activity on the IFN-g gene.

SummaryThe involvement of excessive T helper 1 (Th1) cell functions in the pathogenesis of Behçet's disease (BD) has been reported. We therefore studied

SummaryExcessive Th1 cell function is importantly involved in the pathogenesis of Behcet's disease (BD). We previously found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell specific transcription factor. To investigate immune aberration in the pathogenesis of BD, we studied the expression of Txk and Th1 cytokines in peripheral blood lymphocytes (PBL) and skin lesions in patients with BD. Cytokine production by the lymphocytes was assessed using ELISA. PBL produced excessive Th1 associated cytokines including IFN-g g g

Behcet's disease (BD) is characterized by recurrent attacks of uveitis, oral aphtha, genital ulcers and skin lesions.The etiology and pathogenesis of BD are largely unknown. It has been reported that excessive Th1 cell function is involved in the pathogenesis of BD. Previously, we found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell-specific transcription factor that is involved in the effector function of Th1 cells.Thus, we studied Th1 cytokine production and Txk expression of T-lymphocytes in patients with BD. Peripheral blood lymphocytes produced excessive Th1-associated cytokines including interferon-γ (IFN-γ) and interleukin (IL)-12 in patients with BD. Circulating CD3+ and purified CD4+ T cells expressed excessive Txk protein.The extent of IFN-γ production by the lymphocytes correlated with the expression of Txk protein in the immunoblotting analysis. The majority of cells infiltrating into the skin lesions of patients with BD expressed IFN-γ. IL-12 and IL-18 were found in the mononuclear cell aggregates in the skin and intestinal lesions of those with BD. Lymphocytes accumulating in the skin and intestinal lesions expressed higher levels of Txk as compared with other Th2-associated diseases. IFN-γ, IL-18 and IL-12 detected in skin lesions may induce preferential development of Th1 cells in patients with BD. Collectively,Th1 cells expressing Txk and Th1-associated cytokines may play a critical role in the development of skin and intestinal lesions in patients with BD. This review may serve as a reminder of the importance of excessive Th1 cell function in the pathogenesis of BD and may contribute to the discovery of new molecular targets for the development of a specific therapeutic strategy for BD.