Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis

Nat Med. 2005 Aug;11(8):892-8. doi: 10.1038/nm1269. Epub 2005 Jul 10.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Concanavalin A / toxicity
  • Cytokines / blood
  • Enterotoxins / toxicity*
  • Inflammation / drug therapy*
  • Inflammation / etiology
  • Leukocytes / metabolism
  • Lipopolysaccharides / toxicity
  • Liver / pathology
  • Lymphocytes / metabolism
  • Mice
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Staphylococcal Infections / complications*
  • Staphylococcal Infections / 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*

Substances

  • Cytokines
  • Enterotoxins
  • Lipopolysaccharides
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • Socs3 protein, mouse
  • Stat1 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Concanavalin A
  • enterotoxin B, staphylococcal