The intratracheal administration of endotoxin and cytokines. III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin- and IL-1-induced acute inflammation

Am J Pathol. 1991 Mar;138(3):521-4.


Endotoxin, a lipopolysaccharide (LPS) component of gram-negative bacteria, induces alveolar macrophages to express interleukin-1 (IL-1). Lipopolysaccharide and IL-1 both cause severe acute neutrophilic inflammation in the lung after intratracheal injection, suggesting that LPS-induced IL-1 expression contributes to the pathogenesis of LPS-induced acute inflammation. In the present study, the role of IL-1 in LPS-induced acute pneumonia was investigated by quantitating the acute inflammation occurring at 6 hours after the intratracheal injection of LPS as compared to the same timepoint after the intratracheal coinjection of LPS and IL-1 receptor antagonist (IL-1ra). The IL-1ra was found to inhibit LPS-induced acute inflammation (P greater than 0.0001) as measured by the number of neutrophils recovered in bronchoalveolar lavage. The LPS-induced emigration of neutrophils was inhibited by as much as 45%. Recombinant IL-1 beta-induced neutrophil emigration into the lung was inhibited by 95% when IL-1ra was coinjected intratracheally with IL-1 beta. Coinjection of recombinant IL-1 beta and LPS increased the neutrophilic exodus as compared to the intratracheal injection of either agent alone. Intratracheal injection of LPS induces a progressive increase in IL-1ra mRNA expression in whole-lung RNA preparations, suggesting that endogenous IL-1ra may play an important role as a negative feedback mechanism to downregulate LPS initiated IL-1-mediated acute inflammation. In conclusion IL-1ra inhibits both LPS- and IL-1-induced neutrophilic inflammation and may therefore prove clinically useful as an anti-inflammatory agent for the therapy of either septic or aseptic IL-1-mediated acute inflammation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / pathology
  • Endotoxins / pharmacology*
  • Injections
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / antagonists & inhibitors*
  • Leukocyte Count / drug effects
  • Lung / metabolism
  • Male
  • Neutrophils / pathology
  • Pneumonia / chemically induced*
  • Proteins / pharmacology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred Lew
  • Recombinant Proteins
  • Sialoglycoproteins*
  • Trachea


  • Endotoxins
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • Sialoglycoproteins