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Am J Physiol Gastrointest Liver Physiol 283: G923-G931, 2002. First published July 11, 2002; doi:10.1152/ajpgi.00237.2002
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Vol. 283, Issue 4, G923-G931, October 2002

Interferon-gamma activates EGF receptor and increases TGF-alpha in T84 cells: implications for chloride secretion

Jorge M. Uribe, Declan F. McCole, and Kim E. Barrett

Department of Medicine, University of California San Diego School of Medicine, San Diego, California 92103-8414

IFN-gamma inhibits intestinal Cl- secretion, in part via downregulation of CFTR and Na+-K+-ATPase activity and expression, but the proximal signaling events were unknown. We have shown that transforming growth factor-alpha (TGF-alpha ) inhibits calcium-activated Cl- secretion, and effects of IFN-gamma in other systems are mediated via EGF family members. We tested whether IFN-gamma inhibits Cl- secretion via EGF receptor (EGFr) activation. IFN-gamma increased tyrosine phosphorylation in T84 cells at 24 h, including the EGFr. IFN-gamma also increased cell-associated pro-TGF-alpha , as well as free TGF-alpha in the bathing media. However, whereas IFN-gamma significantly inhibited carbachol-induced Cl- secretion, neither neutralizing antibodies to TGF-alpha nor an EGFr inhibitor (1 µM tyrphostin AG 1478) were able to reverse this inhibitory effect. AG 1478 also failed to reverse IFN-gamma -induced tyrosine phosphorylation of the EGFr, but receptor phosphorylation was attenuated by both the neutralizing antibody to TGF-alpha and PP2, a Src kinase inhibitor. Moreover, PP2 reversed the inhibitory effect of IFN-gamma on Cl- secretion. In total, our findings suggest an increase in functional TGF-alpha and activation of the EGFr in response to IFN-gamma . The release of TGF-alpha and intracellular Src activation likely combine to mediate EGFr phosphorylation, but only Src appears to contribute to the inhibition of transport. Nevertheless, because TGF-alpha plays a role in restitution and repair of the intestinal epithelium after injury, we speculate that these findings reflect a feedback loop whereby IFN-gamma modulates the extent of cytokine-induced intestinal damage.

chloride secretion; cytokines; inflammation; growth factors; mucosal injury


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