Sv. Sitaraman et al., Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediatedby reciprocal secretion of adenosine and IL-6, J CLIN INV, 107(7), 2001, pp. 861-869
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 differentiati
on. Stimulation of T84 monolayers with either apical or basolateral adenosi
ne induces A2b receptor-mediated increase in IL-6 secretion, which is polar
ized to the apical (luminal) compartment. In addition, Salmonella typhimuri
um, TNF-a, and forskolin, known inducers of IL-6 secretion in intestinal ep
ithelial cells, also stimulate IL-G secretion into the apical compartment.
We show that IL6 promoter induction by adenosine occurs through cAMP-mediat
ed 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 adenosin
e signal originates), since such IL-6 is found to induce an intracellular [
Ca++] flux in neutrophils. We conclude that adenosine released in the intes
tinal lumen during active inflammation may induce IL-6 secretion, which is
mediated by cAMP/CREB activation and occurs in an apically polarized fashio
n. This would allow sequential activation of neutrophil degranulation in th
e lumen - a flow of events that would, in an epithelium-dependent fashion,
enhance microbicidal activity of neutrophils as they arrive in the intestin
al lumen.