Inhibition of early T cell cytokine production by arsenic trioxide occurs independently of Nrf2

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a stress-activated transcription factor that induces a variety of cytoprotective genes. Nrf2 also mediates immunosuppressive effects in multiple inflammatory models. Upon activation, Nrf2 dissociates from its repressor protein, Keap1, and translocates to the nucleus where it induces Nrf2 target genes. The Nrf2-Keap1 interaction is disrupted by the environmental toxicant and chemotherapeutic agent arsenic trioxide (ATO). The purpose of the present study was to determine the effects of ATO on early events of T cell activation and the role of Nrf2 in those effects. The Nrf2 target genes Hmox-1, Nqo-1, and Gclc were all upregulated by ATO (1–2 μM) in splenocytes derived from wild-type, but not Nrf2-null, mice, suggesting that Nrf2 is activated by ATO in splenocytes. ATO also inhibited IFNγ, IL-2, and GM-CSF mRNA and protein production in wild-type splenocytes activated with the T cell activator, anti-CD3/anti-CD28. However, ATO also decreased production of these cytokines in activated splenocytes from Nrf2-null mice, suggesting the inhibition is independent of Nrf2. Interestingly, ATO inhibited TNFα protein secretion, but not mRNA expression, in activated splenocytes suggesting the inhibition is due to post-transcriptional modification. In addition, c-Fos DNA binding was significantly diminished by ATO in wild-type and Nrf2-null splenocytes activated with anti-CD3/anti-CD28, consistent with the observed inhibition of cytokine production by ATO. Collectively, this study suggests that although ATO activates Nrf2 in splenocytes, inhibition of early T cell cytokine production by ATO occurs independently of Nrf2 and may instead be due to impaired AP-1 DNA binding.

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases

“…As 2 O 3 exposure resulted in a significant Nrf2-independent inhibition of both mRNA and protein production of IFNγ, IL-2, and GM-CSF in splenocytes ( VanDenBerg et al, 2017 ). It has been also demonstrated that As 2 O 3 inhibited IFN-α secretion in plasmacytoid dendritic cells ( Ye et al, 2020 ).…”

Arsenic, Cadmium and Lead Exposure and Immunologic Function in Workers in Taiwan

“…Cell culture study shows that the chemotherapeutic agent arsenic trioxide could inhibit early T cell cytokine production. [ 7 ]. Negative associations have been found between urine arsenic levels and proliferative response to phytohemaglutinin stimulation, CD4, CD4/CD8 ratio, and IL-2 secretion levels in children [ 1 ].…”

Mercury and arsenic attenuate canonical and non-canonical NLRP3 inflammasome activation

“…Arsenic exposure was been shown to down-regulate gene expression of IL-1β in human and animal cells via inhibition of TLR/IL-1 receptor and NF-κB signaling 6 . Other cytokines, including TNFα, INFγ, IL-2, IL-6, IL-8, IL-10, and IL-17A, are also interrupted by arsenic 6 , 49 , 50 . In macrophages, arsenic inhibits phagocytosis and NO production for digestion of exogenous antigens but induces apoptosis 51 .…”