The critical role for TAK1 in trichloroethylene-induced contact hypersensitivity in vivo and in CD4+ T cell function alteration by trichloroethylene and its metabolites in vitro.

ABSTRACT

Occupational exposure to trichloroethylene (TCE) has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder, which is considered a delayed-type hypersensitivity reaction mediated by antigen-specific T cells. Transforming growth factor-ß activated kinase-1 (TAK1) is essential for regulating the development and effector function of T cells. We hypothesized that disrupting TAK1 activity might inhibit TCE-induced CHS response. In this study, a local lymph node assay was employed to build a CHS model induced by TCE combined with the inducible-TAK1 deletion system to study the effect of TAK1 on it. It was observed that TAK1 deficiency ameliorated the TCE-induced CHS response and was associated with defective T cell expansion and activation and IFN-γ production in vivo. Furthermore, we investigated the effects of TCE and its metabolites trichloroacetic acid (TCA) and dichloroacetic acid (DCA) on CD4+ T cell function and the effect of TAK1 on it in vitro. The results showed that TCE, TCA and DCA augmented the proliferation, activation and differentiation of CD4+ T cells through Jnk MAPK and NF-κB pathways. TAK1 deletion significantly attenuated these effects induced by TCE, TCA or DCA on CD4+ T cells. In conclusion, it is suggested that TAK1 plays a critical role both in TCE-induced CHS response in vivo and in TCE and its metabolite-induced CD4+ T cell activation in vitro. Local inhibition of TAK1 might offer a promising alternative feasible strategy for TCE-induced CHS.