GM‐CSF in association with IL‐1 triggers day‐8 CFU‐S into cell cycle: Role of histamine

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Abstract
Our recent evidence for the requirement of endogeneous histamine in IL‐3‐induced proliferation of day‐8 CFU‐S has prompted us to investigate whether or not GM‐CSF, which shares with IL‐3 the ability to stimulate bone marrow histamine synthesis, could also affect the cell cycle status of CFU‐S via this mediator. We show herein that recombinant GM‐CSF alone fails to trigger day‐8 CFU‐S into S phase, but supports their survival. However, in the same experimental conditions, GM‐CSF in combination with IL‐1 induces a CFU‐S proliferation similar to that obtained in response to IL‐3, while IL‐1 by itself has no effect on this biological activity. We further provide evidence that this phenomenon is completely abolished: (i) by preventing GM‐CSF‐induced histamine synthesis by α‐FMH, the specific inhibitor of histidine decarboxylase (HDC), or (ii) by blocking the binding sites of H2 histamine receptors with their specific antagonist oxmetidine. Similar results are obtained when progenitor‐enriched bone marrow cells are used instead of the unfractionated population. In addition, we provide an argument in support of a histamine receptor modulation by GM‐CSF that could explain the lack of effect of factor‐induced histamine on day‐8 CFU‐S cell cycling. Indeed, the entry of these progenitors into S phase that is normally promoted by dimaprit, a specific histamine H2 receptor agonist, is abolished by a preincubation with GM‐CSF. Taken together, our data support the conclusion that IL‐1 makes CFU‐S sensitive to GM‐CSF‐induced endogeneous histamine that will trigger them into cell cycle, while GM‐CSF alone has no such effect on this biological activity.