TUMOR-NECROSIS-FACTOR INDUCES NEUROENDOCRINE DIFFERENTIATION IN SMALL-CELL LUNG-CANCER CELL-LINES

We studied tumor necrosis factor (TNF)-alpha as a candidate cytokine t o promote neuroendocrine cell differentiation in a nitrosamine-hyperox ia hamster lung injury model. Differential screening identified expres sion of the genes modulated by TNF-alpha preceding neuroendocrine cell differentiation. Undifferentiated small cell lung carcinoma (SCLC) ce ll 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 dec arboxylase mRNA within 5 min after TNF-alpha was added. Nuclear transl ocation of nuclear factor-kappa B immunostaining occurred with TNF-alp ha treatment, suggesting nuclear factor-kappa B involvement in the ind uction of GRP and/or aromatic-L-amino acid decarboxylase gene expressi on. We also demonstrated dense core neurosecretory granules and immuno staining for proGRP and neural cell adhesion molecule in H82 cells aft er 7-14 days of TNF-alpha treatment. We conclude that TNF-alpha can in duce phenotypic features of neuroendocrine cell differentiation in SCL C cell lines. Similar effects of TNF-alpha in vivo may contribute to t he neuroendocrine cell differentiation/hyperplasia associated with man y chronic inflammatory pulmonary diseases.