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

Abstract

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.

• Authors: S V Sitaraman, D Merlin, L Wang, M Wong, A T Gewirtz, M Si-Tahar, J L Madara
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 107 Issue 7 Pg. 861-9 (Apr 2001) ISSN: 0021-9738 [Print] United States
• PMID: 11285305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• Activating Transcription Factors
• Adenosine (metabolism, pharmacology)
• Animals
• Blood Proteins (metabolism)
• COS Cells
• Cell Line
• Chlorocebus aethiops
• Colforsin (metabolism, pharmacology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Dose-Response Relationship, Drug
• Epithelial Cells (cytology, metabolism)
• Interleukin-6 (metabolism)
• Intestinal Mucosa (cytology, 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, pharmacology)