A secreted product of activated neutrophils, NDS (neutrophil-derived secretagogue), elicits a short circuit current (Isc) in epithelial monolayers derived from the human intestinal cell line T84 (J. Clin. Invest. 1991. 87:1474-1477). Here, we identify and characterize the source of this Isc and examine associated signaling pathways. 125I efflux studies suggested that NDS activates an anion conductive channel. Bidirectional 22Na 36Cl flux studies showed that electrogenic Cl- secretion fully accounts for the NDS-induced Isc response. NDS behaved in many respects as a cAMP-mediated secretagogue: NDS did not further increase maximal cAMP-induced Cl- secretion; NDS potentiated Ca(2+)-mediated Cl secretion; and NDS elicited measurable 125I but not 86Rb effluxes. However, NDS did not elicit a detectable rise in intracellular cAMP. Such data suggest that NDS may elicit Cl- secretion by effecting distal events in the cAMP-mediated pathway. Data derived from cell volume assays of isolated guinea pig intestinal crypt cells indicated that NDS also directly elicits Cl- secretion from natural intestinal epithelia. Additionally, since NDS activity is released from PMN by stimuli normally present in the colonic lumen, since NDS is active when applied apically to this model intestinal epithelium, and since the NDS-elicited Isc response is indicative of electrogenic chloride secretion, we speculate NDS may contribute to the secretory diarrhea encountered in many patients with inflammatory intestinal disease.
J L Madara, C Parkos, S Colgan, R J MacLeod, S Nash, J Matthews, C Delp, W Lencer