The cytokines interleukin (IL)-6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitor factor (LIF), oncostatin M (OSM) and probably the recently cloned cytokine cardiotrophin-1, signal, in combination with their specific receptors, through the common signal transducer gp130. Here, we report that the signaling activities of IL-6, IL-11, CNTF and OSM/LIF can be specifically blocked by different anti-gp130 monoclonal antibodies (mAb). Furthermore, we found two mAb, B-P8 and B-S12, which directly activate gp130 independently of the presence of cytokines or their receptors. This agonistic activity includes induction of cytokine-dependent cell proliferation and stimulation of acute-phase protein synthesis in liver cells. Compared to B-P8 mAb, the B-S12 mAb exhibited the strongest agonistic activity, while both mAb are synergistic in their action. This activity could not be blocked by inhibiting mAb against IL-6 and the IL-6 receptor. In contrast to F(ab')2 of B-S12 which still could activate gp130, Fab fragments completely lost their agonistic activity. Activation by tyrosine phosphorylation of the transcription factors Stat1 and APRF/Stat3 was also induced by B-S12 and B-P8, suggesting that both mAb induce homodimerization of gp130. Since hematopoietic stem cells express gp130 on their plasma membrane, it was anticipated that the agonistic anti-gp130 mAb could stimulate the proliferation of these stem cells. Indeed, B-S12 and B-P8 were able to stimulate CD34+ cells. In summary, our data show for the first time that mAb against gp130 can specifically block the action of distinct IL-6-type cytokines that signal through gp130. Such mAb might be of great value for therapeutic applications in diseases where a single cytokine action needs to be inhibited. In addition, the agonistic gp130 mAb may be used as growth factors for maintenance and expansion of stem cells prior to grafting.