Intracellular Delivery of a Cell-Penetrating SOCS1 that Targets IFN-γ Signaling

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Abstract
Suppressor of cytokine signaling–1 (SOCS1) is an intracellular inhibitor of the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway that couples interferon-γ (IFN-γ) signaling to the nucleus. Because several inflammatory diseases are associated with uncontrolled IFN-γ signaling, we engineered a recombinant cell-penetrating SOCS1 (CP-SOCS1) to target this pathway. Here, we show that CP-SOCS1, analogous to endogenous SOCS1, interacted with components of the IFN-γ signaling complex and functionally attenuated the phosphorylation of STAT1, which resulted in the subsequent inhibition of the production of proinflammatory chemokines and cytokines. Thus, controlled, intracellular delivery of recombinant CP-SOCS1 boosted the anti-inflammatory potential of the cell by restoring the homeostatic balance between pro- and anti-inflammatory signaling. This approach to controlling signal transduction has potential use for therapeutic targeting of signaling pathways associated with inflammatory diseases.