Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6
Shanthi V. Sitaraman, … , Mustapha Si-Tahar, James L. Madara
Shanthi V. Sitaraman, … , Mustapha Si-Tahar, James L. Madara
Published April 1, 2001
Citation Information: J Clin Invest. 2001;107(7):861-869. https://doi.org/10.1172/JCI11783.
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Article

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-α, 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

Shanthi V. Sitaraman, Didier Merlin, Lixin Wang, Michelle Wong, Andrew T. Gewirtz, Mustapha Si-Tahar, James L. Madara

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Figure 8

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Schematic representation of epithelial-neutrophil interaction in a crypt...
Schematic representation of epithelial-neutrophil interaction in a crypt abscess. An epithelial monolayer with neutrophils transmigrating to the luminal compartment is shown at the left. Inset shows that adenosine is derived from the enzymatic conversion (mediated by epithelial ectonucleotidase, CD 73) of 5′ AMP released in the lumen by the neutrophils. Adenosine thus released interacts with the adenosine A2b receptor, a G protein–coupled receptor, resulting in an increase in intracellular cAMP that may be involved in the transcriptional activation of IL-6 secretion. IL-6 is preferentially released in the apical compartment and induces intracellular [Ca++] flux in neutrophils, which may be involved in the release of oxygen radicals, elastase, etc., from the neutrophils.