Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6

J Clin Invest. 2001 Apr;107(7):861-9. doi: 10.1172/JCI11783.


Adenosine is formed in the intestinal lumen during active inflammation from neutrophil-derived 5' AMP. Using intestinal epithelial cell line T84, we studied the effect of adenosine on the secretion of IL-6, a proinflammatory cytokine involved in neutrophil degranulation and lymphocyte differentiation. Stimulation of T84 monolayers with either apical or basolateral adenosine induces A2b receptor-mediated increase in IL-6 secretion, which is polarized to the apical (luminal) compartment. In addition, Salmonella typhimurium, TNF-alpha, and forskolin, known inducers of IL-6 secretion in intestinal epithelial cells, also stimulate IL-6 secretion into the apical compartment. We show that IL6 promoter induction by adenosine occurs through cAMP-mediated activation of nuclear cAMP-responsive element-binding protein (CREB). We also show that IL-6 released in the luminal (apical) compartment achieves a sufficient concentration to activate neutrophils (from which the adenosine signal originates), since such IL-6 is found to induce an intracellular [Ca(++)] flux in neutrophils. We conclude that adenosine released in the intestinal lumen during active inflammation may induce IL-6 secretion, which is mediated by cAMP/CREB activation and occurs in an apically polarized fashion. This would allow sequential activation of neutrophil degranulation in the lumen -- a flow of events that would, in an epithelium-dependent fashion, enhance microbicidal activity of neutrophils as they arrive in the intestinal lumen.

Publication types

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

MeSH terms

  • Activating Transcription Factors
  • Adenosine / metabolism*
  • Adenosine / pharmacology
  • Animals
  • Blood Proteins / metabolism
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Colforsin / metabolism
  • Colforsin / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dose-Response Relationship, Drug
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Interleukin-6 / metabolism*
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism*
  • Neutrophils / metabolism*
  • Purinergic P1 Receptor Antagonists
  • Receptor, Adenosine A2B
  • Receptors, Purinergic P1 / metabolism
  • Salmonella typhimurium / metabolism
  • Signal Transduction / physiology*
  • Time Factors
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • Activating Transcription Factors
  • Blood Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Interleukin-6
  • Purinergic P1 Receptor Antagonists
  • Receptor, Adenosine A2B
  • Receptors, Purinergic P1
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Colforsin
  • Adenosine