Tumor necrosis factor-alpha-induced proliferation requires synthesis of granulocyte-macrophage colony-stimulating factor

Objective. Tumor necrosis factor-alpha (TNF-alpha) induces a variety of cel lular responses, some of them being at least seemingly contradictory, Thus, we set out to find differences in the modes of proliferative and apoptotic responses to TNF-alpha. Materials and Methods. We screened a panel of acute myeloid leukemia-derive d cell lines for TNF-alpha-responsiveness. In two lines (OCI-AML-1, OCI-AML -11), TNF-alpha acted as an apoptotic agent; in others (HU-3, M-07e, TF-1), it had the opposite effect, preventing apoptosis and inducing proliferatio n, Direct and indirect signaling mechanisms, including NF-kappa B activatio n and cytokine synthesis, were analyzed. Results. All cell lines tested expressed TNF-alpha receptors I and ZI and r esponded to TNF-alpha by upregulation of intercellular adhesion molecule-1, In contrast to granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-alpha did not activate the MAP kinase and p70S6 kinase pathways, Nevert heless, inhibitors of these pathways clearly reduced the TNF-alpha-induced cell growth, indicating that TNF-alpha-proliferative cells produced a growt h factor that induced proliferation upon stimulation of the above pathways, Anti-GM-CSP antibodies inhibited the TNF-alpha-induced growth, suggesting the presence of an autocrine loop for cell proliferation mediated by GM-CSF , Supporting this notion, TNF-alpha-induced upregulation of GM-CSF mRNA lev els and protein secretion in the TNF-alpha-proliferative, but not in the TN F-alpha-apoptotic cell lines. Conclusion. These data identify GM-CSF synthesis as an early and essential step in TNF-alpha-induced proliferation. We shaw for the first time that TN F-alpha-treated cell lines producing no or only minimal amounts of GM-CSF d emonstrate an apoptotic phenotype, while cell lines with high GM-CSF expres sion rates can escape from growth arrest or even apoptosis, In this context , we discuss arguments pointing at NF-kappa B as regulator of GM-CSF synthe sis and thus indirectly as regulator for the escape of TNF-alpha-induced ap optosis, (C) 2000 International Society for Experimental Hematology, Publis hed by Elsevier Science Inc.