The role of type I and type II tumor necrosis factor (TNF) receptors in the ability of TNF-alpha to transduce a proliferative signal in the human megakaryoblastic leukemic cell line Mo7e.

We investigated the effects of tumor necrosis factor (TNF) alpha on the human megakaryocytic leukemic cell lines Mo7e, Meg-01, and Dami/HEL. Our data show that both type I and type II TNF receptors (TNF-RI and TNF-RII) are expressed on all of these cells, and TNF-alpha significantly stimulates the proliferation of growth factor-dependent Mo7e cells but not of Meg-01 or Dami/HEL cells, which grow in a factor-independent manner. TNF-alpha serves predominantly as a mitogen for Mo7e cell proliferation and does not induce Mo7e cell differentiation. Coincubation with both TNF-alpha and anti-TNF-alpha neutralizing antibody completely abolishes the TNF-alpha-induced proliferation of Mo7e cells. In bioassays, there is no detectable level of other stimulatory cytokines in conditioned medium from Mo7e cells previously stimulated by TNF-alpha, implying that the stimulatory effect of TNF-alpha on Mo7e cells is derived from the direct action of TNF-alpha rather than via the induction of secondary cytokines by TNF-alpha. Flow cytometric studies demonstrated that TNF-alpha binds to Mo7e cells that have been pretreated with either anti-TNF-RI or anti-TNF-RII neutralizing antibody, but TNF-alpha does not bind to cells pre-exposed to both receptor antibodies. However, the incubation of Mo7e cells with either TNF-RI or TNF-RII neutralizing antibodies or with either soluble TNF-RI or TNF-RII inhibits TNF-alpha-induced cell proliferation, indicating the requirement of interactions with both TNF receptors for the mitogenic activity of TNF-alpha. Furthermore, our data suggest that an alternative signaling pathway may be involved in TNF-alpha-induced Mo7e cell proliferation, because the common mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) signaling pathways activated by other cytokines that induce Mo7e cell proliferation are not activated by TNF-alpha.