Interleukin‐6 signal transducer gp130 has specific binding sites for different cytokines as determined by antagonistic and agonistic anti‐gp130 monoclonal antibodies

摘要

AbstractThe 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′)2of 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