Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis.
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.
Jo
Daewoong
D
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, A-5321 MCN, Nashville, Tennessee 37232, USA.
Liu
Danya
D
Yao
Shan
S
Collins
Robert D
RD
Hawiger
Jacek
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000097:blood; D004768:Enterotoxins / Q000633:toxicity*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013203:Staphylococcal Infections / Q000150:complications* / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D016207:Cytokines; D004768:Enterotoxins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D003208:Concanavalin A; C031818:enterotoxin B, staphylococcal