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Effect of trichloroethanol on TLR2 and TLR4/NF-κB-mediated antigen processing and presentation in HLA-B* 13:01-transfected antigen-presenting cells

Trichloroethanol (TCOH), as a metabolite of trichloroethylene, has sensitization in the pathogenesis of trichloroethylene-induced hypersensitivity dermatitis (TIHD) which the human leukocyte antigen (HLA)-B∗13:01 gene is strongly associated with it. However, it is still obscure how TCOH participates in the pathogenesis of TIHD. Here, we demonstrate that TLR2 and TLR4 signaling through MyD88 and TRAF6-dependent pathway could activate NF-κB by promoting degradation of the inhibitor IκB-α to stimulate the process of NF-κB nuclear translocation. Besides, the crucial molecules of antigen processing and presentation, including TAP1, LMP2, LMP7, and HLA-B* 13:01, were all enhanced and the abundance of HLA-B* 13:01 on the surface of CIR-B* 13:01 cells was also up-regulated with the TCOH concentration increasing. Notably, we used 50 μM pyrrolidinedithiocarbamate (ammonium) to effectively inhibit the activation of NF-κB, which could effectively reverse the stimulation of antigen processing and presentation in TCOH-treated CIR-B* 13:01 cells. Taken together, we speculated that TCOH could promote the abundance of HLA complex on the antigen-presenting cells via TLR2 and TLR4/NF-κB to induce the severe reactivation of T lymphocytes, leading to the extreme immune response.

 

Comments：

Based on the research findings presented, it appears that TCOH, a metabolite of trichloroethylene, may contribute to the development of TIHD through activation of the Toll-like receptor (TLR) 2 and TLR4 signaling pathways, leading to the activation of the transcription factor NF-κB. This activation of NF-κB may then lead to the upregulation of important molecules involved in antigen processing and presentation, including TAP1, LMP2, LMP7, and HLA-B*13:01.

Furthermore, the study suggests that TCOH may increase the abundance of HLA-B13:01 on the surface of CIR-B13:01 cells, possibly through the TLR2 and TLR4/NF-κB pathway. The upregulation of HLA-B*13:01 may then lead to the reactivation of T lymphocytes, resulting in an extreme immune response.

The study also suggests that the activation of NF-κB can be effectively inhibited by pyrrolidinedithiocarbamate (ammonium), which can reverse the stimulation of antigen processing and presentation in TCOH-treated CIR-B*13:01 cells. Overall, these findings provide insight into the potential mechanisms underlying TIHD and suggest possible therapeutic targets for this condition.

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S3633 PDTC (Pyrrolidinedithiocarbamate ammonium) PDTC (Pyrrolidinedithiocarbamate ammonium) is a potent nuclear factor-κB (NF-κB) inhibitor that inhibits IκB phosphorylation, blocks NF-κB translocation to the nucleus and reduces the expression of downstream cytokines.

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NF-κB