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Am J Physiol Lung Cell Mol Physiol 275: L311-L321, 1998;
1040-0605/98 $5.00
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Vol. 275, Issue 2, L311-L321, August 1998

Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines

Kathleen J. Haley1, Kirit Patidar2, Fan Zhang2, Rodica L. Emanuel3, and Mary E. Sunday2,3

1 Pulmonary and Critical Care Division, Department of Medicine, and 3 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School; and 2 Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115

We studied tumor necrosis factor (TNF)-alpha as a candidate cytokine to promote neuroendocrine cell differentiation in a nitrosamine-hyperoxia hamster lung injury model. Differential screening identified expression of the genes modulated by TNF-alpha preceding neuroendocrine cell differentiation. Undifferentiated small cell lung carcinoma (SCLC) cell lines NCI-H82 and NCI-H526 were treated with TNF-alpha for up to 2 wk. Both cell lines demonstrated rapid induction of gastrin-releasing peptide (GRP) mRNA; H82 cells also expressed aromatic-L-amino acid decarboxylase mRNA within 5 min after TNF-alpha was added. Nuclear translocation of nuclear factor-kappa B immunostaining occurred with TNF-alpha treatment, suggesting nuclear factor-kappa B involvement in the induction of GRP and/or aromatic-L-amino acid decarboxylase gene expression. We also demonstrated dense core neurosecretory granules and immunostaining for proGRP and neural cell adhesion molecule in H82 cells after 7-14 days of TNF-alpha treatment. We conclude that TNF-alpha can induce phenotypic features of neuroendocrine cell differentiation in SCLC cell lines. Similar effects of TNF-alpha in vivo may contribute to the neuroendocrine cell differentiation/hyperplasia associated with many chronic inflammatory pulmonary diseases.

nuclear factor-kappa B; cell differentiation; gastrin-releasing peptide; aromatic-L-amino acid decarboxylase; neural cell adhesion molecule


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