Cytokine Receptors, Drug Resistance, Oxidative Stress and Cell Death

Throughout my career, my laboratory has studied the mode of action of various cytokines, focusing on the identification and isolation of cytokines, cytokine receptors, and binding proteins. We Isolated and characterized the human interferon alpha, where we revealed its composition of multiple species encoded by diverse genes. Together with my team members Drs. Daniela Novick, Batya Cohen, Soo Hyun Kim, and others, we successfully cloned the ligand-binding subunit of the Type I interferon receptor (IFNAR2) and demonstrated ligand-induced association of IFNAR2 and its accessory receptor subunit IFNAR1 as the mechanism of interferon action. In collaboration with Dr. Charles Dinarello, we identified and cloned IL-18 binding protein (IL-18BP), a natural circulating cytokine inhibitor.

Over the years, we have isolated and identified many circulating soluble receptors, including those of IL-6, IFN-gamma, TNF, Type I interferons, and LDL. Importantly, our investigations uncovered that the LDL receptor and its other family members are the entry ports of vesicular stomatitis virus (VSV) and VSV-G-pseudotyped lentiviral vectors. This observation is highly relevant to gene therapy and to oncolytic virotherapy.

In other studies, we studied the role of C/EBPβ in cell survival and death, with a particular emphasis on tumor drug resistance. We also discovered that chemotherapy and endoplasmic reticulum stress led to the production of leukotrienes in non-immune cells. These leukotrienes then induced the production of reactive oxygen species, leading to oxidative DNA damage and subsequent cell death. These findings revealed an unexpected critical pathway through which major chemotherapeutic agents (5FU, doxorubicin, vincristine) trigger cell death.

In recent years, we have focused on improving gene therapy and oncolytic virotherapy, aiming to achieve cell and tissue specificity. If successful, our studies will reduce to complexity and cost of these procedures by allowing in vivo administration of VSV and VSV-G-based vectors.

The culmination of our studies led to the development of three approved biological drugs (Roferon A, REBIF, and Enbrel). A fourth one, Tadekinig alfa (IL-18BP), is currently in clinical trials.