Methods: Sera was collected from patients with ISM with tryptase ranging from 1-1000 ng/ml. P815 cells were injected i.v. into DBA/2 mice to induce SM. DJ-1 levels were measured by ELISA and ROS by a fluorescent assay.
Results: Patients with ISM showed increased ROS and diminished DJ-1 levels in serum. DJ-1 but not ROS levels reverted towards normal values in patients with advanced ISM. Long-term exposure to SCF or expression of constitutively active mutant KIT in human MC cultures enhanced DJ-1 degradation. In contrast, IL-6, a cytokine which increases in serum with disease severity, induced DJ-1 transcription and promoted ROS release. Injection of mastocytoma cells harboring mutant KIT into mice reproduced the effects of human disease with biphasic changes in serum DJ-1 and increasing elevations in ROS and IL-6 as disease progressed. These effects and disease severity were reversed with anti-IL-6 receptor blocking antibody.
Conclusions: The link between IL-6 production in the context of aberrant KIT signaling to dysregulation of DJ-1 and ROS homeostasis suggests that IL-6 contributes to redox imbalance and worsening of ISM and provides potential targets for therapeutic intervention.