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Arsenic is a toxic element that affects normal cellular processes. Arsenic causes poisoning of the glycolysis and TCA cycle by inhibiting their key enzymes while it also suppresses the hematopoietic and immune system as well as it is also associated with cancer.
Chronic and acute exposure to the arsenic is commonly associated with leukopenia, and anemia mediated by the damage to the hematopoiesis while it causes immunotoxicity mediated by the damage to the hormonal and cell-mediated immunity. Arsenic also leads to the apoptosis of the immune cells including B lymphocytes, macrophages, and T lymphocytes.
The ability of arsenic to suppress the hematopoiesis and to induce the immunotoxicity on different immune cells suggest that arsenic and its compounds (arsenicals) may involve the inhibition of the cytokine receptors and their downstream signaling pathways. Because of the importance of the JAK-STAT pathway in the cytokine receptor-mediated signaling in the immune cells, researchers have studied whether the arsenic interferes with the JAK-STATE pathway of the cytokine receptor.
Arsenic inactivates the JAK-STAT signaling pathway
For this study, researchers had used IL-6 (cytokine) as a model system in which they studied an inhibitory effect of the arsenic on the activation of the JAK-STAT signaling pathway. They found that arsenite inhibits the JAK-STAT signaling pathway by interfering with the kinase activity of the JAK. The inhibitory effect of the arsenite was measured by the electrophoretic mobility shift assay (EMSA) and immunoblotting analysis.
During the transient exposure of the sodium arsenite for the 30 min, researchers found a decrease in the activity of the IL-6-induced STAT3 with the increase in arsenite concentration. While in the case of the long-term exposure of the sodium arsenite for the 48 hours, it led to the same result as found in the transient exposure of the system to the high dose of the arsenite. These results reveal that exposure to the arsenite affects the STAT3 signaling pathway and the effect is cumulative and time-dependent.
Researchers exposed the IL-6 model system to the different levels of the cadmium for 48 hours to differentiate the arsenic inhibition of STAT3 from heavy metal toxicity. However, researchers didn’t find inactivation of the STAT3 by cadmium neither did they find any effects of the cadmium on the JAK-STAT signaling pathway.
Arsenic inhibits the tyrosine phosphorylation
Phosphorylation of the key tyrosine residue (Y705) of the STAT3 is necessary for the STAT3 activation and DNA binding while phosphorylation of the key serine residue (S727) of the STAT3 is necessary to regulate its activity and tyrosine phosphorylation. Therefore, researchers analyzed the effect of arsenite in the phosphorylation of the key tyrosine and serine residues of the STAT3 by immunoblotting.
Results were consistent with the EMSA result during which the addition of the cytokine IL-6 alone to the system caused phosphorylation of the Y705 while arsenite exposure caused inhibition of that tyrosine residue (Y705). Therefore, arsenite blocks the IL-6-induced activation of the STAT3 by inhibiting the tyrosine phosphorylation of the Y705 residue.
To know whether the arsenite could also disrupt the DNA binding ability of the active STAT3 or not, researchers used a whole-cell extract transfected with an active STAT (STAT3C). Using the EMSA, they found that STAT3C co-migrated with a labeled probe even in the absence of the cytokine. This result reveals that arsenite disrupts the STAT3 activity and occur only upstream in this signaling.
Arsenic affects the regulatory feedback loops of the JAK-STAT pathway
Researchers also analyzed whether arsenic exposure affects the integrity of the JAK-STAT signaling pathway and its regulatory feedback loop. For this purpose, they used an mRNA of a suppressor of the cytokine signaling, SOCS. Using the ribonuclease protection assay (RPA), they found that transcription of the SOCS genes is induced when the system was supplemented with cytokines and is highly dependent on the activity of the STATs. While supplementing the system with arsenite, researchers observed the inhibition of the SOCS expression.
The expression of the SOCS gene leads to the formation of the SOCS protein that suppresses the JAK-STAT signaling pathway. And the above experiment confirms that arsenite, exposed to the system turns off the JAK-STAT signaling pathway.
Arsenic affects activities of both STAT3 and JAK
JAK1 is located upstream of the STAT3 in the cytokine receptor-induced signaling pathway. Therefore, to determine whether arsenite affects the JAK, researchers evaluated the effect of arsenite on the JAK activity induced by the IL-6. They found that arsenite exposure causes inhibition of the IL-6-induced autophosphorylation of the key tyrosine residues of the JAK.
JAK-STAT inhibition is independent of the cytokine receptor interaction
To determines whether the effect of arsenite on JAK tyrosine kinase is related to the receptor-ligand interaction, they introduced the wild type JAK1 to the JAK-/- Hela cells. They found that suppression of the JAK1 activity and tyrosine phosphorylation of the STAT3 demonstrating inhibition of the JAK-STAT signaling pathway is independent of the cytokine receptor interaction.
JAK-STAT inhibition is independent of the MAP kinase pathway
Researchers have also demonstrated the ability of arsenite to activate the MAP kinase pathway. However, inactivation of the MAP kinase is not related to the arsenite-induced inhibition of the JAK-STAT pathway. To illustrate this relation, researchers used specific inhibitors of the Erks, p38, and JNKs and found that inhibition of the MAP kinase pathway did not affect the inhibition of the JAK-STAT pathway by arsenite. This finding reveals that arsenite selectively targets the JAK-STAT signaling pathway and the inhibition is independent of the MAP kinase pathway.
JAK-STAT signaling pathway plays an essential role in the regulation of cell proliferation, differentiation, the progression of the cell cycle, and the hematopoietic cells. Therefore, any alteration in the JAK-STAT pathway leads to the development of tumorigenesis, immunotoxicity, and defective hematopoiesis. Sodium arsenite possesses an inhibitory activity that can inhibit the JAK-STAT signaling pathway. Sodium arsenite-induced inhibition of the JAK-STAT is independent of the cytokine receptor interaction and leads to the defective hematopoiesis, immunotoxicity, and development of the tumorigenesis.
Reference: Oncogene (Arsenic inhibition of the JAK-STAT pathway)
Article DOI: 10.1038/sj.onc.1207466