Intracellular delivery of a cell-penetrating SOCS1 that targets IFN-gamma signaling.
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-gamma (IFN-gamma) signaling to the nucleus. Because several inflammatory diseases are associated with uncontrolled IFN-gamma 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-gamma 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.
DiGiandomenico
Antonio
A
Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232-2363, USA.
Wylezinski
Lukasz S
LS
Hawiger
Jacek
J
D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism* / Q000494:pharmacology
C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma