In vivo modulation of the inflammatory response by nonsteroidal antiinflammatory drug-related compounds that trigger L-selectin shedding

Eur J Immunol. 2013 Jan;43(1):55-64. doi: 10.1002/eji.201242805. Epub 2012 Oct 26.


Diphenylamine-based nonsteroidal antiinflammatory drugs (NSAIDs) are able to cause in vitro the shedding of L-selectin. The aim of this work was to determine the physio-logic relevance of L-selectin shedding in the antiinflammatory effect exerted by NSAIDs in vivo. Chemical compounds structurally related to NSAIDs - including diphenyl-amine, N-phenylanthranilic acid (N-Ph), diphenylacetic acid - as well as the traditional NSAID indomethacin were studied using the zymosan air-pouch mouse model. Animals intramuscularly pretreated with indomethacin or N-Ph, but not with diphenyl-amine or diphenylacetic acid, showed a significant dose-dependent reduction in the number of neutrophils compared with untreated animals (N-Ph, IC50 = 6.7 mg/kg). Except for indomethacin, none of these compounds caused any significant reduction in cyclooxygenase-1 activity in vivo. In flow chamber experiments, N-Ph reduced the capability of human neutrophils to pass across the endothelial barrier by interfering with leukocyte rolling step on HUVEC. N-Ph, but not diphenylacetic acid, induced activation-independent L-selectin shedding in mouse neutrophils. Interestingly, N-Ph exerted an antiinflammatory effect similar to that of the anti-L-selectin blocking antibody Mel-14, although no additive action was observed when both compounds were combined. These data suggest that the L-selectin shedding induced by NSAIDs may be involved in the antiinflammatory action exerted by these compounds in clinical settings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage*
  • Cell Line
  • Cyclooxygenase 1 / metabolism
  • Diphenylamine / administration & dosage*
  • Diphenylamine / analogs & derivatives
  • Disease Models, Animal
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / immunology*
  • Humans
  • Inflammation / immunology
  • L-Selectin / metabolism*
  • Leukocyte Count
  • Leukocyte Rolling / drug effects
  • Male
  • Mice
  • Mice, Inbred Strains
  • Neutrophils / drug effects*
  • Neutrophils / immunology


  • Anti-Inflammatory Agents, Non-Steroidal
  • L-Selectin
  • Diphenylamine
  • Cyclooxygenase 1