Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis

• Published in: Nature medicine Vol. 11; no. 8; pp. 892 - 898
• Main Authors: Hawiger, Jacek, Jo, Daewoong, Liu, Danya, Yao, Shan, Collins, Robert D
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-08-2005
• Subjects: Animals; Apoptosis - drug effects; Concanavalin A - toxicity; Cytokines - blood; Enterotoxins - toxicity; Inflammation - drug therapy; Inflammation - etiology; Lethal effects; Leukocytes - metabolism; Lipopolysaccharides - toxicity; Liver; Liver - pathology; Lymphocytes; Lymphocytes - metabolism; Mice; Pathogens; Protected animals; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Signal Transduction - drug effects; Staphylococcal Infections - complications; Staphylococcal Infections - metabolism; STAT1 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - metabolism; Suppressor of Cytokine Signaling Proteins - pharmacokinetics; Suppressor of Cytokine Signaling Proteins - pharmacology; Suppressor of Cytokine Signaling Proteins - therapeutic use
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1269

Suppressor of cytokine signaling (SOCS) 3 attenuates proinflammatory signaling mediated by the signal transducer and activator of transcription (STAT) family of proteins. But acute inflammation can occur after exposure to pathogen-derived inducers staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS), or the lectin concanavalin A (ConA), suggesting that physiologic levels of SOCS3 are insufficient to stem proinflammatory signaling under pathogenic circumstances. To test this hypothesis, we developed recombinant cell-penetrating forms of SOCS3 (CP-SOCS3) for intracellular delivery to counteract SEB-, LPS- and ConA-induced inflammation. We found that CP-SOCS3 was distributed in multiple organs within 2 h and persisted for at least 8 h in leukocytes and lymphocytes. CP-SOCS3 protected animals from lethal effects of SEB and LPS by reducing production of inflammatory cytokines and attenuating liver apoptosis and hemorrhagic necrosis. It also reduced ConA-induced liver apoptosis. Thus, replenishing the intracellular stores of SOCS3 with CP-SOCS3 effectively suppresses the devastating effects of acute inflammation.