Constitutive KIT Activity and IL-6 Production in Mast Cells Alters Levels of Reactive Oxygen Species (ROS) and the Scavenger Protein DJ-1 in Mastocytosis
Monday, March 7, 2016: 2:30 PM
Room 515A (Convention Center)
Dokyun Kim, PhD, , , , , , , , ,
Rationale: Mastocytosis is characterized by hyperproliferation of mast cells (MCs) which is mostly associated with activating mutations in KIT, the stem cell factor (SCF) receptor. DJ-1, a scavenger protein of ROS in MCs and other tissue cells, has been linked to oxidative damage in atopic dermatitis, cancer and neurogenerative diseases.  We examined whether DJ-1 is dysregulated in indolent systemic mastocytosis (ISM) and the impact of KIT mutations on DJ-1 and ROS levels.

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.