Activation of gp130 signaling in vivo by the IL-6 super-agonist K-7/D-6 accelerates repopulation of lymphoid organs after irradiation

Stimulation of the gp130 signaling pathway by IL-6 is known to contribute s ignificantly to hematopoietic expansion in vitro, mostly in combination wit h other cytokines. In the present study we have investigated whether a simi lar effect can be observed also in vivo using shortterm assays in which irr adiated mice were analyzed for repopulation of lymphoid organs. Mice were i njected with a combination of soluble IL-6R alpha either with wild-type (wt ) human IL-6 or with an IL-6 variant, called K-7/D-6, that shows a 70-fold higher IL-6R alpha affinity. We observed that while wt IL-6 was able to ind uce a partial effect only in combination with IL-3, K-7/D-6 bypassed the ne ed for IL-3 and yielded complete recovery. In lethally irradiated mice reco nstituted with syngeneic bone marrow cells K-7/D-6 strongly accelerated the repopulation of thymus and spleen and hastened blood neutrophil recovery. These results underscore the potential of the gp130 signaling pathway in he matopoietic reconstitution after myeloablative regimens and open the possib ility to fully exploit it with a super-active IL-6 variant.