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The Epidermal Growth Factor-Like Growth Factor Amphiregulin Is Strongly Induced by the Adenosine 3',5'-Monophosphate Pathway in Various Cell Types

Biotechnology Center of Oslo, University of Oslo (C.C.J., J.M.E., K.T.), Research Institute for Internal Medicine (A.Y., P.A.), and Section of Clinical Immunology and Infectious Diseases (P.A.), National Hospital, University of Oslo; and Department of Tumor Biology, Norwegian Radium Hospital (A.H.R.), N-0317 Oslo, Norway

Address all correspondence and requests for reprints to: Dr. Kjetil Taskén, Biotechnology Center of Oslo, University of Oslo, P.O. Box 1125, Blindern, N-0317 Oslo, Norway. E-mail: kjetil.tasken{at}biotek.uio.no.

We examined the cAMP-mediated regulation of the epidermal growth factor-like growth factor amphiregulin (AR) in T cells and observed a strong cAMP-induced up-regulation of AR mRNA in a time- and concentration-dependent manner independent of T cell activation. This regulation may be mediated in part through activation of a cAMP-responsive element in the AR promoter, because the cAMP-responsive element conferred cAMP responsiveness to a luciferase reporter in Jurkat TAg cells. Similar effects of AR mRNA induction were seen in T cells treated with cAMP-elevating agents such as prostaglandin E₂ and forskolin as well as with the phosphodiesterase inhibitors rolipram and isobutylmethylxanthine. Furthermore, the induction of AR mRNA by cAMP was strongly suppressed by a protein kinase A type I-selective inhibitor, whereas treatment with an exchange protein directly activated by cAMP-specific agonist did not increase AR levels. In addition, an increase in AR gene transcripts by cAMP was seen in MCF-7 mammary carcinoma cells and H295R adrenal cells. Moreover, the potent cAMP-mediated induction of AR mRNA resulted in increased secretion (5-fold) of AR from T cells. Furthermore, supernatants from cAMP-stimulated T cells containing secreted AR induced phosphorylated MAPK in OVCAR-3 carcinoma cells. In conclusion, our data suggest that AR is under strong regulation by the cAMP pathway in various cell types, and that prostaglandin E₂- and cAMP-induced AR secretion from T cells may be highly relevant in a microenvironment consisting of tumor cells and infiltrated immune cells, because AR by activating the MAPK pathway through a paracrine route may contribute to proliferation of tumor cells and thus add to neoplastic processes.

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