Reversing systemic inflammatory response syndrome with chemokine receptor pepducins

Nat Med. 2005 Jun;11(6):661-5. doi: 10.1038/nm1245. Epub 2005 May 8.


We describe a new therapeutic approach for the treatment of lethal sepsis using cell-penetrating lipopeptides-termed pepducins-that target either individual or multiple chemokine receptors. Interleukin-8 (IL-8), a ligand for the CXCR1 and CXCR2 receptors, is the most potent endogenous proinflammatory chemokine in sepsis. IL-8 levels rise in blood and lung fluids to activate neutrophils and other cells, and correlate with shock, lung injury and high mortality. We show that pepducins derived from either the i1 or i3 intracellular loops of CXCR1 and CXCR2 prevent the IL-8 response of both receptors and reverse the lethal sequelae of sepsis, including disseminated intravascular coagulation and multi-organ failure in mice. Conversely, pepducins selective for CXCR4 cause a massive leukocytosis that does not affect survival. CXCR1 and CXCR2 pepducins conferred nearly 100% survival even when treatment was postponed, suggesting that our approach might be beneficial in the setting of advanced disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Female
  • Humans
  • Interleukin-8 / physiology
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Neutrophils / drug effects
  • Peptides / pharmacology*
  • Protein Conformation
  • Protein Subunits
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / physiology
  • Receptors, Interleukin-8A / antagonists & inhibitors*
  • Receptors, Interleukin-8A / chemistry
  • Receptors, Interleukin-8A / physiology
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Receptors, Interleukin-8B / chemistry
  • Receptors, Interleukin-8B / physiology
  • Systemic Inflammatory Response Syndrome / drug therapy*
  • Systemic Inflammatory Response Syndrome / physiopathology*


  • Interleukin-8
  • Peptides
  • Protein Subunits
  • Receptors, CXCR4
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B