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 1

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IL-6 induction by adenosine. T84 monolayers were prewashed in HBSS and e...
IL-6 induction by adenosine. T84 monolayers were prewashed in HBSS and equilibrated at 37°C for 20 minutes. Adenosine (Ado; 100 μM) was added to the apical (Ap) or basolateral (Bs) compartment. After an incubation period of 5.5–6 hours at 37°C, IL-6 was measured in the apical or basolateral compartment as described in Methods. Values are expressed as pg/ml. Data represent the responses observed in three separate experiments plotted as mean ± SD, n = 3 samples per treatment group. Footnotes represent values significantly different from monolayers treated with vehicle alone, AP < 0.001, BP < 0.05. (a) Monolayers treated with either vehicle or adenosine. (b) Monolayers treated with either adenosine (100 μM) or adenosine plus 8-SPT (100 μM). Ap, apical; Bs, basolateral.